艾滋病毒Vpr蛋白抑制KSHV裂解性周期复制：GSK-3β信号通路的作用
|
摘要
目的:研究人类免疫缺陷病毒1型(human immunodeficiency virus type 1,HIV-1)病毒蛋白R(viral protein R,Vpr)对卡波济肉瘤相关疱疹病毒(Kaposi’s sarcoma-associated herpesvirus,KSHV)裂解性周期复制的影响,并对此过程所涉及到的信号通路进行鉴定。
方法:1、包装和鉴定含Vpr基因的重组慢病毒,并进行滴度测定。以重组慢病毒Vpr感染原发性渗出性淋巴瘤细胞系【primary effusion lymphoma,PEL,又称体腔淋巴瘤(body cavity-based lymphoma,BCBL)】来源的BCBL-1细胞,反转录RCR(reverse transcription PCR,RT-PCR)和免疫印迹(Western blot)分别检测Vpr基因的mRNA转录和蛋白表达。2、用病毒感染方法将Vpr基因导入PEL细胞系,采用实时荧光定量聚合酶链式反应(real-time quantitative polymerase chain reaction,real-time PCR)、RT-PCR和Western blot检测KSHV裂解期基因的mRNA转录和蛋白表达;进一步检测感染后细胞上清中KSHV病毒含量,并以RT-PCR和Western blot检测经上清感染的Vero细胞中KSHV裂解期和潜伏期基因mRNA转录和蛋白表达;将重组慢病毒Vpr感染PEL细胞系,然后转染含KSHV ORF50/ORF73基因启动子的虫荧光素酶(Luciferase)报告质粒,检测Luciferase活性。3、以重组慢病毒Vpr感染BCBL-1细胞,提取细胞总RNA进行人信号通路发现者PCR芯片操作,采用Western blot对基因芯片结果进行验证,加入信号通路上关键蛋白激酶抑制剂、过表达突变质粒后再检测KSHV裂解期蛋白的表达。
结果:1、携带Vpr基因的慢病毒获得成功包装,病毒滴度为4×107Tu/ml。重组慢病毒Vpr感染BCBL-1细胞后可检测到Vpr基因的转录和表达。2、Vpr蛋白不但可以显著抑制BCBL-1细胞中KSHV裂解期基因ORF50(编码KSHV“分子开关”蛋白)、ORF26(编码KSHV次要衣壳蛋白)mRNA的转录,而且还能够显著降低KSHV裂解期蛋白病毒白细胞介素6(viral Interleukin-6,vIL-6)和KSHV复制与转录激活子(replication and transcription activator,Rta,即“分子开关”蛋白)的表达。BCBL-1细胞中过表达Vpr蛋白一方面能够显著下调KSHV的病毒拷贝数,同时明显地降低了Vero细胞中KSHV ORF73/LANA【潜伏相关核抗原,(latency-associated nuclear antigen)】、ORF26 mRNA的转录及vIL-6蛋白的表达。Vpr蛋白能够直接抑制ORF50和ORF73基因启动子的活化。3、Vpr蛋白降低了GSK-3β【糖原合成酶激酶3β(glycogen synthase kinase 3β,GSK-3β)】信号通路中GSK-3β的磷酸化水平,应用GSK-3β抑制剂LiCl及过表达其突变质粒GSK-3β-S9A后,Vpr蛋白对KSHV vIL-6的抑制作用分别被进一步增强和部分阻断。Vpr蛋白下调了PTEN(phosphatase and tensin homolog deleted on chromosome ten)信号通路中PTEN的磷酸化水平,应用其过表达质粒pTEN后,Vpr蛋白对KSHV vIL-6的抑制作用被进一步增强。Vpr蛋白还降低了Ras/c-Raf/MEK/ERK信号通路中c-Raf、MEK1/2及ERK1/2的磷酸化水平。
结论:1、含Vpr基因重组慢病毒可以有效地感染BCBL-1细胞,并在其中大量表达目的蛋白。2、Vpr蛋白能够显著抑制KSHV裂解性周期复制及子代病毒颗粒的释放,作用机制可能是通过抑制ORF50和ORF73基因启动子的活化。3、Vpr蛋白通过抑制GSK-3β及PTEN信号通路的活化下调KSHV复制,Ras/c-Raf/MEK/ERK信号通路可能参与调控Vpr蛋白抑制KSHV复制过程。推测在AIDS相关的KS(AIDS-KS)患者体内,Vpr蛋白有可能通过抑制KSHV裂解性周期复制来避免KSHV感染细胞后过早地被免疫清除,从而有利于潜伏感染的形成和肿瘤的发生。
Objective: To evaluate the effect of human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) on the lytic cycle replication of Kaposi’s sarcoma-associated herpesvirus (KSHV) and identify the signaling pathway(s) involved in this process.
Methods: 1. Recombinant lentivirus containing HIV-1 Vpr gene was packaged and identified, and simultaneously the viral titer was checked. The mRNA transcription and protein expression of Vpr gene in BCBL-1 (body cavity-based lymphoma, BCBL, or primary effusion lymphoma, PEL) cells infected with the recombinant lentivirus were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. 2. The mRNA transcription and protein expression of lytic phase genes of KSHV in PEL cells infected with the lentivirus were detected by real-time quantitative PCR (Real-time PCR) and Western blot, respectively. Then the supernatants of infected BCBL-1 were collected to measure KSHV viral particles as well as to infect vero cells. Subsequently the mRNA transcription and protein expression of lytic phase genes of KSHV in vero cells were also detected by RT-PCR and Western blot, respectively. Furthermore, the luciferase reporter assay was performed after PEL cells were infected with recombinant lentivirus carrying Vpr gene and further transfected with luciferase reporter plasmid carrying KSHV ORF50 or ORF73 gene promoter. 3. The human signal transduction pathwayfinder PCR array was performed using the RNA of BCBL-1 cells infected with recombinant lentivirus carrying Vpr gene and the results were verified by Western blot. Finally, the lytic protein expression of KSHV was further determined by Western blot after the addition of the specific inhibitor or overexpression of mutant plasmid.
Results: 1. The recombinant lentivirus carrying Vpr gene was packaged successfully with the viral titer of 4×107 Tu/ml. And the mRNA transcription and protein expression of Vpr gene could be detected in BCBL-1 infected with the recombinant lentivirus. 2. The overexpression of Vpr protein remarkably decreased not only the lytic mRNA transcription of ORF50 (switch gene of KSHV cycle replication) and ORF26 (encoding KSHV minor capsid protein), but also the lytic proteins of viral interleukin-6 (vIL-6) and replication and transcription activator (Rta). Meanwhile, the overexpression of Vpr in BCBL-1 cells significantly downregulated the copies of KSHV viral particles as well as the mRNA transcription of ORF73/LANA (latent-associated nuclear antigen), ORF26 and the protein expression of vIL-6 in vero cells. In addition, the Vpr protein inhibited the activation of KSHV ORF50 and ORF73 promoters directly. 3. Overexpression of Vpr protein decreased the phosphorylation of glycogen synthase kinase 3β(GSK-3β) in BCBL-1 cells. Addition of LiCl, the specific inhibitor of GSK-3β, or transfection of GSK-3β-S9A construct, the overexpression plasmid of GSK-3β, reinforced or partially blocked the effect of Vpr-downregulated expression of KSHV vIL-6. Vpr protein also decreased the phosphorylation of PTEN and the transfection of overexpression plasmid of PTEN also reinforced the effect of Vpr-downregulated expression of KSHV vIL-6. Finally, Vpr protein also inhibited the phosphorylation of c-Raf、MEK1/2 and ERK1/2 of MAKP signaling pathway .
Conclusions: 1. Recombinant lentivirus containing Vpr gene could efficiently infect BCBL-1 cells, and Vpr protein expressed in BCBL-1 cells. 2. The Vpr protein significantly downregulated the lytic cycle replication of KSHV by inhibiting the activation of ORF50 and ORF73 promoters. 3. Vpr repressed KSHV replication by inhibiting the activation of GSK-3βand PTEN signaling pathways. Ras/c-Raf/MEK/ERK MAPK pathway might also play a role in modulation of Vpr-inhibited KSHV replication. These data suggest that in AIDS-related KS (AIDS-KS) patients, Vpr protein may help KSHV to escape from the immune clearance by inhibiting KSHV lytic replication, which facilitate the establishment of latent infection and tumor formation.
方法:1、包装和鉴定含Vpr基因的重组慢病毒,并进行滴度测定。以重组慢病毒Vpr感染原发性渗出性淋巴瘤细胞系【primary effusion lymphoma,PEL,又称体腔淋巴瘤(body cavity-based lymphoma,BCBL)】来源的BCBL-1细胞,反转录RCR(reverse transcription PCR,RT-PCR)和免疫印迹(Western blot)分别检测Vpr基因的mRNA转录和蛋白表达。2、用病毒感染方法将Vpr基因导入PEL细胞系,采用实时荧光定量聚合酶链式反应(real-time quantitative polymerase chain reaction,real-time PCR)、RT-PCR和Western blot检测KSHV裂解期基因的mRNA转录和蛋白表达;进一步检测感染后细胞上清中KSHV病毒含量,并以RT-PCR和Western blot检测经上清感染的Vero细胞中KSHV裂解期和潜伏期基因mRNA转录和蛋白表达;将重组慢病毒Vpr感染PEL细胞系,然后转染含KSHV ORF50/ORF73基因启动子的虫荧光素酶(Luciferase)报告质粒,检测Luciferase活性。3、以重组慢病毒Vpr感染BCBL-1细胞,提取细胞总RNA进行人信号通路发现者PCR芯片操作,采用Western blot对基因芯片结果进行验证,加入信号通路上关键蛋白激酶抑制剂、过表达突变质粒后再检测KSHV裂解期蛋白的表达。
结果:1、携带Vpr基因的慢病毒获得成功包装,病毒滴度为4×107Tu/ml。重组慢病毒Vpr感染BCBL-1细胞后可检测到Vpr基因的转录和表达。2、Vpr蛋白不但可以显著抑制BCBL-1细胞中KSHV裂解期基因ORF50(编码KSHV“分子开关”蛋白)、ORF26(编码KSHV次要衣壳蛋白)mRNA的转录,而且还能够显著降低KSHV裂解期蛋白病毒白细胞介素6(viral Interleukin-6,vIL-6)和KSHV复制与转录激活子(replication and transcription activator,Rta,即“分子开关”蛋白)的表达。BCBL-1细胞中过表达Vpr蛋白一方面能够显著下调KSHV的病毒拷贝数,同时明显地降低了Vero细胞中KSHV ORF73/LANA【潜伏相关核抗原,(latency-associated nuclear antigen)】、ORF26 mRNA的转录及vIL-6蛋白的表达。Vpr蛋白能够直接抑制ORF50和ORF73基因启动子的活化。3、Vpr蛋白降低了GSK-3β【糖原合成酶激酶3β(glycogen synthase kinase 3β,GSK-3β)】信号通路中GSK-3β的磷酸化水平,应用GSK-3β抑制剂LiCl及过表达其突变质粒GSK-3β-S9A后,Vpr蛋白对KSHV vIL-6的抑制作用分别被进一步增强和部分阻断。Vpr蛋白下调了PTEN(phosphatase and tensin homolog deleted on chromosome ten)信号通路中PTEN的磷酸化水平,应用其过表达质粒pTEN后,Vpr蛋白对KSHV vIL-6的抑制作用被进一步增强。Vpr蛋白还降低了Ras/c-Raf/MEK/ERK信号通路中c-Raf、MEK1/2及ERK1/2的磷酸化水平。
结论:1、含Vpr基因重组慢病毒可以有效地感染BCBL-1细胞,并在其中大量表达目的蛋白。2、Vpr蛋白能够显著抑制KSHV裂解性周期复制及子代病毒颗粒的释放,作用机制可能是通过抑制ORF50和ORF73基因启动子的活化。3、Vpr蛋白通过抑制GSK-3β及PTEN信号通路的活化下调KSHV复制,Ras/c-Raf/MEK/ERK信号通路可能参与调控Vpr蛋白抑制KSHV复制过程。推测在AIDS相关的KS(AIDS-KS)患者体内,Vpr蛋白有可能通过抑制KSHV裂解性周期复制来避免KSHV感染细胞后过早地被免疫清除,从而有利于潜伏感染的形成和肿瘤的发生。
Objective: To evaluate the effect of human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) on the lytic cycle replication of Kaposi’s sarcoma-associated herpesvirus (KSHV) and identify the signaling pathway(s) involved in this process.
Methods: 1. Recombinant lentivirus containing HIV-1 Vpr gene was packaged and identified, and simultaneously the viral titer was checked. The mRNA transcription and protein expression of Vpr gene in BCBL-1 (body cavity-based lymphoma, BCBL, or primary effusion lymphoma, PEL) cells infected with the recombinant lentivirus were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. 2. The mRNA transcription and protein expression of lytic phase genes of KSHV in PEL cells infected with the lentivirus were detected by real-time quantitative PCR (Real-time PCR) and Western blot, respectively. Then the supernatants of infected BCBL-1 were collected to measure KSHV viral particles as well as to infect vero cells. Subsequently the mRNA transcription and protein expression of lytic phase genes of KSHV in vero cells were also detected by RT-PCR and Western blot, respectively. Furthermore, the luciferase reporter assay was performed after PEL cells were infected with recombinant lentivirus carrying Vpr gene and further transfected with luciferase reporter plasmid carrying KSHV ORF50 or ORF73 gene promoter. 3. The human signal transduction pathwayfinder PCR array was performed using the RNA of BCBL-1 cells infected with recombinant lentivirus carrying Vpr gene and the results were verified by Western blot. Finally, the lytic protein expression of KSHV was further determined by Western blot after the addition of the specific inhibitor or overexpression of mutant plasmid.
Results: 1. The recombinant lentivirus carrying Vpr gene was packaged successfully with the viral titer of 4×107 Tu/ml. And the mRNA transcription and protein expression of Vpr gene could be detected in BCBL-1 infected with the recombinant lentivirus. 2. The overexpression of Vpr protein remarkably decreased not only the lytic mRNA transcription of ORF50 (switch gene of KSHV cycle replication) and ORF26 (encoding KSHV minor capsid protein), but also the lytic proteins of viral interleukin-6 (vIL-6) and replication and transcription activator (Rta). Meanwhile, the overexpression of Vpr in BCBL-1 cells significantly downregulated the copies of KSHV viral particles as well as the mRNA transcription of ORF73/LANA (latent-associated nuclear antigen), ORF26 and the protein expression of vIL-6 in vero cells. In addition, the Vpr protein inhibited the activation of KSHV ORF50 and ORF73 promoters directly. 3. Overexpression of Vpr protein decreased the phosphorylation of glycogen synthase kinase 3β(GSK-3β) in BCBL-1 cells. Addition of LiCl, the specific inhibitor of GSK-3β, or transfection of GSK-3β-S9A construct, the overexpression plasmid of GSK-3β, reinforced or partially blocked the effect of Vpr-downregulated expression of KSHV vIL-6. Vpr protein also decreased the phosphorylation of PTEN and the transfection of overexpression plasmid of PTEN also reinforced the effect of Vpr-downregulated expression of KSHV vIL-6. Finally, Vpr protein also inhibited the phosphorylation of c-Raf、MEK1/2 and ERK1/2 of MAKP signaling pathway .
Conclusions: 1. Recombinant lentivirus containing Vpr gene could efficiently infect BCBL-1 cells, and Vpr protein expressed in BCBL-1 cells. 2. The Vpr protein significantly downregulated the lytic cycle replication of KSHV by inhibiting the activation of ORF50 and ORF73 promoters. 3. Vpr repressed KSHV replication by inhibiting the activation of GSK-3βand PTEN signaling pathways. Ras/c-Raf/MEK/ERK MAPK pathway might also play a role in modulation of Vpr-inhibited KSHV replication. These data suggest that in AIDS-related KS (AIDS-KS) patients, Vpr protein may help KSHV to escape from the immune clearance by inhibiting KSHV lytic replication, which facilitate the establishment of latent infection and tumor formation.
引文
[1] Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma[J]. Science, 1994, 266(5192): 1865-1869.
[2] Katano H, Sata T. Human herpesvirus 8 virology, epidemiology and related diseases[J]. Jpn J Infect Dis, 2000, 53(4): 137-155.
[3] Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1)[J]. J Virol, 1998, 72(2): 1005-1012.
[4] Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, Parry JP, Peruzzi D, Edelman IS, Chang Y, Moore PS. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8)[J]. Proc Natl Acad Sci U S A, 1996, 93(25): 14862-14867.
[5] Decker LL, Shankar P, Khan G, Freeman RB, Dezube BJ, Lieberman J, Thorley-Lawson DA. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients[J]. J Exp Med, 1996, 184(1): 283-288.
[6] Sturzl M, Blasig C, Schreier A, Neipel F, Hohenadl C, Cornali E, Ascherl G, Esser S, Brockmeyer NH, Ekman M, Kaaya EE, Tschachler E, Biberfeld P. Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma[J]. Int J Cancer, 1997, 72(1): 68-71.
[7] Henry M, Uthman A, Geusau A, Rieger A, Furci L, Lazzarin A, Lusso P, Tschachler E. Infection of circulating CD34+ cells by HHV-8 in patients with Kaposi's sarcoma[J]. J Invest Dermatol, 1999, 113(4): 613-616.
[8] Mesri EA, Cesarman E, Arvanitakis L, Rafii S, Moore MA, Posnett DN, Knowles DM, Asch AS. Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus is a new transmissible virus that infects B cells[J]. J Exp Med, 1996, 183(5): 2385-2390.
[9] Lu C, Zeng Y, Huang Z, Huang L, Qian C, Tang G, Qin D. Human herpesvirus 6 activates lytic cycle replication of Kaposi's sarcoma-associatedherpesvirus[J]. Am J Pathol, 2005, 166(1): 173-183.
[10] Varthakavi V, Browning PJ, Spearman P. Human immunodeficiency virus replication in a primary effusion lymphoma cell line stimulates lytic-phase replication of Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 1999, 73(12): 10329-10338.
[11] Vieira J, O'Hearn P, Kimball L, Chandran B, Corey L. Activation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) lytic replication by human cytomegalovirus[J]. J Virol, 2001, 75(3): 1378-1386.
[12] Qin D, Zeng Y, Qian C, Huang Z, Lv Z, Cheng L, Yao S, Tang Q, Chen X, Lu C. Induction of lytic cycle replication of Kaposi's sarcoma-associated herpesvirus by herpes simplex virus type 1: involvement of IL-10 and IL-4[J]. Cell Microbiol, 2008, 10(3): 713-728.
[13] Beral V. Epidemiology of Kaposi's sarcoma[J]. Cancer Surv, 1991, 10: 5-22.
[14] Poznansky MC, Coker R, Skinner C, Hill A, Bailey S, Whitaker L, Renton A, Weber J. HIV positive patients first presenting with an AIDS defining illness: characteristics and survival[J]. BMJ, 1995, 311(6998): 156-158.
[15] Ariyoshi K, Schim van der Loeff M, Cook P, Whitby D, Corrah T, Jaffar S, Cham F, Sabally S, O'Donovan D, Weiss RA, Schulz TF, Whittle H. Kaposi's sarcoma in the Gambia, West Africa is less frequent in human immunodeficiency virus type 2 than in human immunodeficiency virus type 1 infection despite a high prevalence of human herpesvirus 8[J]. J Hum Virol, 1998, 1(3): 193-199.
[16] Delli Bovi P, Donti E, Knowles DM, 2nd, Friedman-Kien A, Luciw PA, Dina D, Dalla-Favera R, Basilico C. Presence of chromosomal abnormalities and lack of AIDS retrovirus DNA sequences in AIDS-associated Kaposi's sarcoma[J]. Cancer Res, 1986, 46(12 Pt 1): 6333-6338.
[17] Barillari G, Gendelman R, Gallo RC, Ensoli B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence[J]. Proc Natl Acad Sci U S A, 1993, 90(17): 7941-7945.
[18] Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC. Release, uptake, and effects of extracellular humanimmunodeficiency virus type 1 Tat protein on cell growth and viral transactivation[J]. J Virol, 1993, 67(1): 277-287.
[19] Watson K, Gooderham NJ, Davies DS, Edwards RJ. Interaction of the transactivating protein HIV-1 tat with sulphated polysaccharides[J]. Biochem Pharmacol, 1999, 57(7): 775-783.
[20] Frankel AD, Young JA. HIV-1: fifteen proteins and an RNA[J]. Annu Rev Biochem, 1998, 67: 1-25.
[21] Felzien LK, Woffendin C, Hottiger MO, Subbramanian RA, Cohen EA, Nabel GJ. HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator[J]. Proc Natl Acad Sci U S A, 1998, 95(9): 5281-5286.
[22] Muller B, Tessmer U, Schubert U, Krausslich HG. Human immunodeficiency virus type 1 Vpr protein is incorporated into the virion in significantly smaller amounts than gag and is phosphorylated in infected cells[J]. J Virol, 2000, 74(20): 9727-9731.
[23] Muthumani K, Kudchodkar S, Papasavvas E, Montaner LJ, Weiner DB, Ayyavoo V. HIV-1 Vpr regulates expression of beta chemokines in human primary lymphocytes and macrophages[J]. J Leukoc Biol, 2000, 68(3): 366-372.
[24] Bachand F, Yao XJ, Hrimech M, Rougeau N, Cohen EA. Incorporation of Vpr into human immunodeficiency virus type 1 requires a direct interaction with the p6 domain of the p55 gag precursor[J]. J Biol Chem, 1999, 274(13): 9083-9091.
[25] Lavallee C, Yao XJ, Ladha A, Gottlinger H, Haseltine WA, Cohen EA. Requirement of the Pr55gag precursor for incorporation of the Vpr product into human immunodeficiency virus type 1 viral particles[J]. J Virol, 1994, 68(3): 1926-1934.
[26] Sawaya BE, Khalili K, Gordon J, Taube R, Amini S. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome[J]. J Biol Chem, 2000, 275(45): 35209-35214.
[27] Chang F, Re F, Sebastian S, Sazer S, Luban J. HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes[J]. Mol Biol Cell, 2004, 15(4): 1793-1801.
[28] Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection[J]. Genes Dev, 1998, 12(2): 175-185.
[29] Rogel ME, Wu LI, Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection[J]. J Virol, 1995, 69(2): 882-888.
[30] Ramanathan MP, Curley E, 3rd, Su M, Chambers JA, Weiner DB. Carboxyl terminus of hVIP/mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling[J]. J Biol Chem, 2002, 277(49): 47854-47860.
[31] Jowett JB, Xie YM, Chen IS. The presence of human immunodeficiency virus type 1 Vpr correlates with a decrease in the frequency of mutations in a plasmid shuttle vector[J]. J Virol, 1999, 73(9): 7132-7137.
[32] Piller SC, Ewart GD, Jans DA, Gage PW, Cox GB. The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons[J]. J Virol, 1999, 73(5): 4230-4238.
[33] Levy DN, Refaeli Y, MacGregor RR, Weiner DB. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1[J]. Proc Natl Acad Sci U S A, 1994, 91(23): 10873-10877.
[34] Henklein P, Bruns K, Sherman MP, Tessmer U, Licha K, Kopp J, de Noronha CM, Greene WC, Wray V, Schubert U. Functional and structural characterization of synthetic HIV-1 Vpr that transduces cells, localizes to the nucleus, and induces G2 cell cycle arrest[J]. J Biol Chem, 2000, 275(41): 32016-32026.
[35] Sherman MP, Schubert U, Williams SA, de Noronha CM, Kreisberg JF, Henklein P, Greene WC. HIV-1 Vpr displays natural protein-transducing properties: implications for viral pathogenesis[J]. Virology, 2002, 302(1): 95-105.
[36] Zeng Y, Zhang X, Huang Z, Cheng L, Yao S, Qin D, Chen X, Tang Q, Lv Z, Zhang L, Lu C. Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: role of JAK/STAT signaling[J]. J Virol, 2007, 81(5): 2401-2417.
[37] Chen X, Cheng L, Jia X, Zeng Y, Yao S, Lv Z, Qin D, Fang X, Lei Y, Lu C.Human immunodeficiency virus type 1 Tat accelerates Kaposi sarcoma-associated herpesvirus Kaposin A-mediated tumorigenesis of transformed fibroblasts in vitro as well as in nude and immunocompetent mice[J]. Neoplasia, 2009, 11(12): 1272-1284.
[38] Guo J, Sartor M, Karyala S, Medvedovic M, Kann S, Puga A, Ryan P, Tomlinson CR. Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice[J]. Toxicol Appl Pharmacol, 2004, 194(1): 79-89.
[39] Aoki Y, Tosato G. HIV-1 Tat enhances Kaposi sarcoma-associated herpesvirus (KSHV) infectivity[J]. Blood, 2004, 104(3): 810-814.
[40] Krylov DM, Nasmyth K, Koonin EV. Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs[J]. Curr Biol, 2003, 13(2): 173-177.
[41] Benko Z, Liang D, Agbottah E, Hou J, Taricani L, Young PG, Bukrinsky M, Zhao RY. Antagonistic interaction of HIV-1 Vpr with Hsf-mediated cellular heat shock response and Hsp16 in fission yeast (Schizosaccharomyces pombe)[J]. Retrovirology, 2007, 4: 16.
[42] Huard S, Elder RT, Liang D, Li G, Zhao RY. Human immunodeficiency virus type 1 Vpr induces cell cycle G2 arrest through Srk1/MK2-mediated phosphorylation of Cdc25[J]. J Virol, 2008, 82(6): 2904-2917.
[43] Warbrick E, Fantes PA. A conserved eukaryotic cell cycle control[J]. Bioessays, 1988, 8(6): 202-204.
[44] Csikasz-Nagy A, Battogtokh D, Chen KC, Novak B, Tyson JJ. Analysis of a generic model of eukaryotic cell-cycle regulation[J]. Biophys J, 2006, 90(12): 4361-4379.
[45] Goh WC, Manel N, Emerman M. The human immunodeficiency virus Vpr protein binds Cdc25C: implications for G2 arrest[J]. Virology, 2004, 318(1): 337-349.
[46] He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity[J]. J Virol, 1995, 69(11): 6705-6711.
[47]方欣卢,曹戌,李久明,秦娣,吕志刚. HIV-I编码病毒蛋白R基因在真核细胞中的表达及其表达蛋白对KSHV溶解性周期复制的影响[J].南京医科大学学报(自然科学版), 2008, 28(9): 8.
[48] McAllister SC, Hansen SG, Messaoudi I, Nikolich-Zugich J, Moses AV. Increased efficiency of phorbol ester-induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus during S phase[J]. J Virol, 2005, 79(4): 2626-2630.
[49] Varthakavi V, Smith RM, Deng H, Sun R, Spearman P. Human immunodeficiency virus type-1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus through induction of KSHV Rta[J]. Virology, 2002, 297(2): 270-280.
[50] Merat R, Amara A, Lebbe C, de The H, Morel P, Saib A. HIV-1 infection of primary effusion lymphoma cell line triggers Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation[J]. Int J Cancer, 2002, 97(6): 791-795.
[51] Strathdee SA, Hogg RS, O'Shaughnessy MV, Montaner JS, Schechter MT. A decade of research on the natural history of HIV infection: Part 2. Cofactors[J]. Clin Invest Med, 1996, 19(2): 121-130.
[52] Aoki Y, Tosato G. Interactions between HIV-1 Tat and KSHV[J]. Curr Top Microbiol Immunol, 2007, 312: 309-326.
[53] Levy DN, Refaeli Y, Weiner DB. Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency[J]. J Virol, 1995, 69(2): 1243-1252.
[54] Ensoli B, Buonaguro L, Barillari G. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. [J].J Virol. 1993;67(4):277-287.
[55] Refaeli Y, Levy DN, Weiner DB. The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product[J]. Proc Natl Acad Sci U S A, 1995, 92(8): 3621-3625.
[56] Hogan TH, Nonnemacher MR, Krebs FC, Henderson A, Wigdahl B. HIV-1 Vpr binding to HIV-1 LTR C/EBP cis-acting elements and adjacent regions is sequence-specific[J]. Biomed Pharmacother, 2003, 57(1): 41-48.
[57] Wang L, Mukherjee S, Jia F, Narayan O, Zhao LJ. Interaction of virion protein Vpr of human immunodeficiency virus type 1 with cellulartranscription factor Sp1 and trans-activation of viral long terminal repeat[J]. J Biol Chem, 1995, 270(43): 25564-25569.
[58] Lan K, Kuppers DA, Verma SC, Robertson ES. Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency[J]. J Virol, 2004, 78(12): 6585-6594.
[59] Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll-like receptor signaling controls reactivation of KSHV from latency[J]. Proc Natl Acad Sci U S A, 2009, 106(28): 11725-11730.
[60] Vieira J, O'Hearn PM. Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression[J]. Virology, 2004, 325(2): 225-240.
[61] Chang J, Renne R, Dittmer D, Ganem D. Inflammatory cytokines and the reactivation of Kaposi's sarcoma-associated herpesvirus lytic replication[J]. Virology, 2000, 266(1): 17-25.
[62] Zoeteweij JP, Rinderknecht AS, Davis DA, Yarchoan R, Blauvelt A. Minimal reactivation of Kaposi's sarcoma-associated herpesvirus by corticosteroids in latently infected B cell lines[J]. J Med Virol, 2002, 66(3): 378-383.
[63] Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G. A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus[J]. Proc Natl Acad Sci U S A, 1998, 95(18): 10866-10871.
[64] Martin D, Gutkind JS. Human tumor-associated viruses and new insights into the molecular mechanisms of cancer[J]. Oncogene, 2008, 27 Suppl 2: S31-42.
[65] Lu F, Day L, Gao SJ, Lieberman PM. Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi's sarcoma-associated herpesvirus lytic transcription[J]. J Virol, 2006, 80(11): 5273-5282.
[66] Lan K, Kuppers DA, Robertson ES. Kaposi's sarcoma-associated herpesvirus reactivation is regulated by interaction of latency-associated nuclear antigen with recombination signal sequence-binding protein Jkappa, the major downstream effector of the Notch signaling pathway[J]. J Virol, 2005, 79(6): 3468-3478.
[67] Renne R, Zhong W, Herndier B, McGrath M, Abbey N, Kedes D, Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus8) in culture[J]. Nat Med, 1996, 2(3): 342-346.
[68] Li Z, Tan F, Thiele CJ. Inactivation of glycogen synthase kinase-3beta contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells[J]. Mol Cancer Ther, 2007, 6(12 Pt 1): 3113-3121.
[69] Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development[J]. Proc Natl Acad Sci U S A, 1996, 93(16): 8455-8459.
[70] Brown HJ, Song MJ, Deng H, Wu TT, Cheng G, Sun R. NF-kappaB inhibits gammaherpesvirus lytic replication[J]. J Virol, 2003, 77(15): 8532-8540.
[71] Keller SA, Schattner EJ, Cesarman E. Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells[J]. Blood, 2000, 96(7): 2537-2542.
[72] Grossmann C, Ganem D. Effects of NFkappaB activation on KSHV latency and lytic reactivation are complex and context-dependent[J]. Virology, 2008, 375(1): 94-102.
[73] Qian LW, Xie J, Ye F, Gao SJ. Kaposi's sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases[J]. J Virol, 2007, 81(13): 7001-7010.
[74] Cohen A, Brodie C, Sarid R. An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus[J]. J Gen Virol, 2006, 87(Pt 4): 795-802.
[75] Ford PW, Bryan BA, Dyson OF, Weidner DA, Chintalgattu V, Akula SM. Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency[J]. J Gen Virol, 2006, 87(Pt 5): 1139-1144.
[76] Fujimuro M, Nakaso K, Nakashima K, Sadanari H, Hisanori I, Teishikata Y, Hayward SD, Yokosawa H. Multiplex PCR-based DNA array for simultaneous detection of three human herpesviruses, EVB, CMV and KSHV[J]. Exp Mol Pathol, 2006, 80(2): 124-131.
[77] Montaner S. Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma[J]. Cell Cycle, 2007, 6(4): 438-443.
[78] Bryan MA, Socha MT, Tomlinson DJ. Supplementing intensively grazed late-gestation and early-lactation dairy cattle with chromium[J]. J Dairy Sci,2004, 87(12): 4269-4277.
[79] Hackett ML, Yang M, Anderson CS, Horrocks JA, House A. Pharmaceutical interventions for emotionalism after stroke[J]. Cochrane Database Syst Rev, 2: CD003690.
[80] Mingyan Y, Xinyong L, De Clercq E. NF-kappaB: the inducible factors of HIV-1 transcription and their inhibitors[J]. Mini Rev Med Chem, 2009, 9(1): 60-69.
[81] Dabrowska A, Kim N, Aldovini A. Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes[J]. J Immunol, 2008, 181(12): 8460-8477.
[82] Witte V, Laffert B, Gintschel P, Krautkramer E, Blume K, Fackler OT, Baur AS. Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta raft recruitment leading to activation of ERK1/2 but not NF kappa B[J]. J Immunol, 2008, 181(12): 8425-8432.
[83] Cui M, Huang Y, Zhao Y, Zheng J. Transcription factor FOXO3a mediates apoptosis in HIV-1-infected macrophages[J]. J Immunol, 2008, 180(2): 898-906.
[84] Sgarbanti M, Arguello M, tenOever BR, Battistini A, Lin R, Hiscott J. A requirement for NF-kappaB induction in the production of replication-competent HHV-8 virions[J]. Oncogene, 2004, 23(34): 5770-5780.
[85] Albert F, Anderson SG, Anderson GA, Betts SM, Gibson DJ, Hagmann CA, Hall J, Johnson MS, Messerly MJ, Semenov VA, Shverdin MY, Tremaine AM, Hartemann FV, Siders CW, McNabb DP, Barty CP. Isotope-specific detection of low-density materials with laser-based monoenergetic gamma-rays[J]. Opt Lett, 35(3): 354-356.
[1] Tungaturthi PK, Sawaya BE, Ayyavoo V, Murali R, Srinivasan A. HIV-1 Vpr: genetic diversity and functional features from the perspective of structure[J]. DNA Cell Biol, 2004, 23(4): 207-222.
[2] Anderson JL, Hope TJ. HIV accessory proteins and surviving the host cell[J]. Curr HIV/AIDS Rep, 2004, 1(1): 47-53.
[3] Felzien LK, Woffendin C, Hottiger MO, Subbramanian RA, Cohen EA, Nabel GJ. HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator[J]. Proc Natl Acad Sci U S A, 1998, 95(9): 5281-5286.
[4] Muller B, Tessmer U, Schubert U, Krausslich HG. Human immunodeficiency virus type 1 Vpr protein is incorporated into the virion in significantly smaller amounts than gag and is phosphorylated in infected cells[J]. J Virol, 2000, 74(20): 9727-9731.
[5] Muthumani K, Kudchodkar S, Papasavvas E, Montaner LJ, Weiner DB, Ayyavoo V. HIV-1 Vpr regulates expression of beta chemokines in human primary lymphocytes and macrophages[J]. J Leukoc Biol, 2000, 68(3): 366-372.
[6] Bachand F, Yao XJ, Hrimech M, Rougeau N, Cohen EA. Incorporation of Vpr into human immunodeficiency virus type 1 requires a direct interaction with the p6 domain of the p55 gag precursor[J]. J Biol Chem, 1999, 274(13): 9083-9091.
[7] Lavallee C, Yao XJ, Ladha A, Gottlinger H, Haseltine WA, Cohen EA. Requirement of the Pr55gag precursor for incorporation of the Vpr product into human immunodeficiency virus type 1 viral particles[J]. J Virol, 1994, 68(3): 1926-1934.
[8] Sawaya BE, Khalili K, Gordon J, Taube R, Amini S. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome[J]. J Biol Chem, 2000, 275(45): 35209-35214.
[9] Chang F, Re F, Sebastian S, Sazer S, Luban J. HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes[J]. Mol Biol Cell, 2004, 15(4): 1793-1801.
[10] Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection[J]. Genes Dev, 1998, 12(2): 175-185.
[11] Rogel ME, Wu LI, Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection[J]. J Virol, 1995, 69(2): 882-888.
[12] Ramanathan MP, Curley E, 3rd, Su M, Chambers JA, Weiner DB. Carboxyl terminus of hVIP/mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling[J]. J Biol Chem, 2002, 277(49): 47854-47860.
[13] Jowett JB, Xie YM, Chen IS. The presence of human immunodeficiency virus type 1 Vpr correlates with a decrease in the frequency of mutations in a plasmid shuttle vector[J]. J Virol, 1999, 73(9): 7132-7137.
[14] Piller SC, Ewart GD, Jans DA, Gage PW, Cox GB. The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons[J]. J Virol, 1999, 73(5): 4230-4238.
[15] Somasundaran M, Sharkey M, Brichacek B, Luzuriaga K, Emerman M, Sullivan JL, Stevenson M. Evidence for a cytopathogenicity determinant in HIV-1 Vpr[J]. Proc Natl Acad Sci U S A, 2002, 99(14): 9503-9508.
[16] Roumier T, Vieira HL, Castedo M, Ferri KF, Boya P, Andreau K, Druillennec S, Joza N, Penninger JM, Roques B, Kroemer G. The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway[J]. Cell Death Differ, 2002, 9(11): 1212-1219.
[17] Srinivasan A, Ayyavoo V, Mahalingam S, Kannan A, Boyd A, Datta D, KalyanaramanVS, Cristillo A, Collman RG, Morellet N, Sawaya BE, Murali R. A comprehensive analysis of the naturally occurring polymorphisms in HIV-1 Vpr: potential impact on CTL epitopes[J]. Virol J, 2008, 5: 99.
[18] Jenkins Y, McEntee M, Weis K, Greene WC. Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways[J]. J Cell Biol, 1998, 143(4): 875-885.
[19] Le Rouzic E, Mousnier A, Rustum C, Stutz F, Hallberg E, Dargemont C, Benichou S. Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1[J]. J Biol Chem, 2002, 277(47): 45091-45098.
[20] Schang LM. The cell cycle, cyclin-dependent kinases, and viral infections: new horizons and unexpected connections[J]. Prog Cell Cycle Res, 2003, 5: 103-124.
[21] Suzuki T, Yamamoto N, Nonaka M, Hashimoto Y, Matsuda G, Takeshima SN, Matsuyama M, Igarashi T, Miura T, Tanaka R, Kato S, Aida Y. Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr-Importin alpha interactions as a novel HIV-1 therapy[J]. Biochem Biophys Res Commun, 2009, 380(4): 838-843.
[22] Gallay P, Stitt V, Mundy C, Oettinger M, Trono D. Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import[J]. J Virol, 1996, 70(2): 1027-1032.
[23] Gallay P, Hope T, Chin D, Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway[J]. Proc Natl Acad Sci U S A, 1997, 94(18): 9825-9830.
[24] Nitahara-Kasahara Y, Kamata M, Yamamoto T, Zhang X, Miyamoto Y, Muneta K, Iijima S, Yoneda Y, Tsunetsugu-Yokota Y, Aida Y. Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages[J]. J Virol, 2007, 81(10): 5284-5293.
[25] Le Rouzic E, Benichou S. The Vpr protein from HIV-1: distinct roles along the viral life cycle[J]. Retrovirology, 2005, 2: 11.
[26] Zeitler B, Weis K. The FG-repeat asymmetry of the nuclear pore complex is dispensable for bulk nucleocytoplasmic transport in vivo[J]. J Cell Biol, 2004, 167(4): 583-590.
[27] de Noronha CM, Sherman MP, Lin HW, Cavrois MV, Moir RD, Goldman RD, Greene WC. Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr[J]. Science, 2001, 294(5544): 1105-1108.
[28] Basavapathruni A, Anderson KS. Reverse transcription of the HIV-1 pandemic[J].FASEB J, 2007, 21(14): 3795-3808.
[29] Li Y, Zhang Z, Wakefield JK, Kang SM, Morrow CD. Nucleotide substitutions within U5 are critical for efficient reverse transcription of human immunodeficiency virus type 1 with a primer binding site complementary to tRNA(His)[J]. J Virol, 1997, 71(9): 6315-6322.
[30] Gao L, Balakrishnan M, Roques BP, Bambara RA. Insights into the multiple roles of pausing in HIV-1 reverse transcriptase-promoted strand transfers[J]. J Biol Chem, 2007, 282(9): 6222-6231.
[31] Sun Y, Pinchuk LM, Agy MB, Clark EA. Nuclear import of HIV-1 DNA in resting CD4+ T cells requires a cyclosporin A-sensitive pathway[J]. J Immunol, 1997, 158(1): 512-517.
[32] Chen R, Le Rouzic E, Kearney JA, Mansky LM, Benichou S. Vpr-mediated incorporation of UNG2 into HIV-1 particles is required to modulate the virus mutation rate and for replication in macrophages[J]. J Biol Chem, 2004, 279(27): 28419-28425.
[33] Mansky LM, Preveral S, Selig L, Benarous R, Benichou S. The interaction of vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 In vivo mutation rate[J]. J Virol, 2000, 74(15): 7039-7047.
[34] Chen R, Wang H, Mansky LM. Roles of uracil-DNA glycosylase and dUTPase in virus replication[J]. J Gen Virol, 2002, 83(Pt 10): 2339-2345.
[35] Berkhout B, de Ronde A. APOBEC3G versus reverse transcriptase in the generation of HIV-1 drug-resistance mutations[J]. AIDS, 2004, 18(13): 1861-1863.
[36] Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, Wei X, Jiang C, Kirchherr JL, Gao F, Anderson JA, Ping LH, Swanstrom R, Tomaras GD, Blattner WA, Goepfert PA, Kilby JM, Saag MS, Delwart EL, Busch MP, Cohen MS, Montefiori DC, Haynes BF, Gaschen B, Athreya GS, Lee HY, Wood N, Seoighe C, Perelson AS, Bhattacharya T, Korber BT, Hahn BH, Shaw GM. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection[J]. Proc Natl Acad Sci U S A, 2008, 105(21): 7552-7557.
[37] Priet S, Navarro JM, Gros N, Querat G, Sire J. Functional role of HIV-1 virion-associated uracil DNA glycosylase 2 in the correction of G:U mispairs to G:C pairs[J]. J Biol Chem, 2003, 278(7): 4566-4571.
[38] Mansky LM. The mutation rate of human immunodeficiency virus type 1 is influenced by the vpr gene[J]. Virology, 1996, 222(2): 391-400.
[39] Bouhamdan M, Benichou S, Rey F, Navarro JM, Agostini I, Spire B, Camonis J, Slupphaug G, Vigne R, Benarous R, Sire J. Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme[J]. J Virol, 1996, 70(2): 697-704.
[40] Belzile JP, Duisit G, Rougeau N, Mercier J, Finzi A, Cohen EA. HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase[J]. PLoS Pathog, 2007, 3(7): e85.
[41] Elder RT, Yu M, Chen M, Zhu X, Yanagida M, Zhao Y. HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25[J]. Virology, 2001, 287(2): 359-370.
[42] Goh WC, Rogel ME, Kinsey CM, Michael SF, Fultz PN, Nowak MA, Hahn BH, Emerman M. HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo[J]. Nat Med, 1998, 4(1): 65-71.
[43] Krylov DM, Nasmyth K, Koonin EV. Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs[J]. Curr Biol, 2003, 13(2): 173-177.
[44] Benko Z, Liang D, Agbottah E, Hou J, Taricani L, Young PG, Bukrinsky M, Zhao RY. Antagonistic interaction of HIV-1 Vpr with Hsf-mediated cellular heat shock response and Hsp16 in fission yeast (Schizosaccharomyces pombe)[J]. Retrovirology, 2007, 4: 16.
[45] Huard S, Elder RT, Liang D, Li G, Zhao RY. Human immunodeficiency virus type 1 Vpr induces cell cycle G2 arrest through Srk1/MK2-mediated phosphorylation of Cdc25[J]. J Virol, 2008, 82(6): 2904-2917.
[46] Warbrick E, Fantes PA. A conserved eukaryotic cell cycle control[J]. Bioessays, 1988, 8(6): 202-204.
[47] Csikasz-Nagy A, Battogtokh D, Chen KC, Novak B, Tyson JJ. Analysis of a generic model of eukaryotic cell-cycle regulation[J]. Biophys J, 2006, 90(12): 4361-4379.
[48] Goh WC, Manel N, Emerman M. The human immunodeficiency virus Vpr protein binds Cdc25C: implications for G2 arrest[J]. Virology, 2004, 318(1): 337-349.
[49] He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity[J]. J Virol, 1995, 69(11): 6705-6711.
[50] Kino T, Gragerov A, Valentin A, Tsopanomihalou M, Ilyina-Gragerova G, Erwin-CohenR, Chrousos GP, Pavlakis GN. Vpr protein of human immunodeficiency virus type 1 binds to 14-3-3 proteins and facilitates complex formation with Cdc25C: implications for cell cycle arrest[J]. J Virol, 2005, 79(5): 2780-2787.
[51] Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals[J]. Genes Dev, 1998, 12(19): 2973-2983.
[52] Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, Washburn MP, Skowronski J. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle[J]. Proc Natl Acad Sci U S A, 2007, 104(28): 11778-11783.
[53] Wen X, Duus KM, Friedrich TD, de Noronha CM. The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor[J]. J Biol Chem, 2007, 282(37): 27046-27057.
[54] Higa LA, Zhang H. Stealing the spotlight: CUL4-DDB1 ubiquitin ligase docks WD40-repeat proteins to destroy[J]. Cell Div, 2007, 2: 5.
[55] Jin J, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1[J]. Mol Cell, 2006, 23(5): 709-721.
[56] Rialland M, Sola F, Santocanale C. Essential role of human CDT1 in DNA replication and chromatin licensing[J]. J Cell Sci, 2002, 115(Pt 7): 1435-1440.
[57] Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis[J]. Annu Rev Cell Dev Biol, 1999, 15: 269-290.
[58] Green DR. Apoptotic pathways: paper wraps stone blunts scissors[J]. Cell, 2000, 102(1): 1-4.
[59] Andersen JL, Le Rouzic E, Planelles V. HIV-1 Vpr: mechanisms of G2 arrest and apoptosis[J]. Exp Mol Pathol, 2008, 85(1): 2-10.
[60] Chang LJ, Chen CH, Urlacher V, Lee TZ. Differential apoptosis effects of primate lentiviral Vpr and Vpx in mammalian cells[J]. J Biomed Sci, 2000, 7(4): 322-333.
[61] Conti L, Matarrese P, Varano B, Gauzzi MC, Sato A, Malorni W, Belardelli F, Gessani S. Dual role of the HIV-1 vpr protein in the modulation of the apoptotic response of T cells[J]. J Immunol, 2000, 165(6): 3293-3300.
[62] Stewart SA, Poon B, Jowett JB, Xie Y, Chen IS. Lentiviral delivery of HIV-1 Vpr protein induces apoptosis in transformed cells[J]. Proc Natl Acad Sci U S A, 1999, 96(21): 12039-12043.
[63] Yedavalli VS, Shih HM, Chiang YP, Lu CY, Chang LY, Chen MY, Chuang CY, Dayton AI, Jeang KT, Huang LM. Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1[J]. J Virol, 2005, 79(21): 13735-13746.
[64] Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, Costantini P, Druillennec S, Hoebeke J, Briand JP, Irinopoulou T, Daugas E, Susin SA, Cointe D, Xie ZH, Reed JC, Roques BP, Kroemer G. The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore[J]. J Exp Med, 2000, 191(1): 33-46.
[65] Jacotot E, Ferri KF, El Hamel C, Brenner C, Druillennec S, Hoebeke J, Rustin P, Metivier D, Lenoir C, Geuskens M, Vieira HL, Loeffler M, Belzacq AS, Briand JP, Zamzami N, Edelman L, Xie ZH, Reed JC, Roques BP, Kroemer G. Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2[J]. J Exp Med, 2001, 193(4): 509-519.
[66] Kim HE, Du F, Fang M, Wang X. Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1[J]. Proc Natl Acad Sci U S A, 2005, 102(49): 17545-17550.
[67] Muthumani K, Hwang DS, Desai BM, Zhang D, Dayes N, Green DR, Weiner DB. HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells[J]. J Biol Chem, 2002, 277(40): 37820-37831.
[68] Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC. Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP[J]. J Biol Chem, 2003, 278(10): 8091-8098.
[69] Arunagiri C, Macreadie I, Hewish D, Azad A. A C-terminal domain of HIV-1 accessory protein Vpr is involved in penetration, mitochondrial dysfunction and apoptosis of human CD4+ lymphocytes[J]. Apoptosis, 1997, 2(1): 69-76.
[70] Zhu Y, Gelbard HA, Roshal M, Pursell S, Jamieson BD, Planelles V. Comparison of cell cycle arrest, transactivation, and apoptosis induced by the simian immunodeficiency virus SIVagm and human immunodeficiency virus type 1 vpr genes[J]. J Virol, 2001, 75(8): 3791-3801.
[71] Kino T, Chrousos GP. Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?[J]. Ann N Y Acad Sci, 2004, 1024: 153-167.
[72] Poon B, Chang MA, Chen IS. Vpr is required for efficient Nef expression fromunintegrated human immunodeficiency virus type 1 DNA[J]. J Virol, 2007, 81(19): 10515-10523.
[73] Balasubramanyam A, Mersmann H, Jahoor F, Phillips TM, Sekhar RV, Schubert U, Brar B, Iyer D, Smith EO, Takahashi H, Lu H, Anderson P, Kino T, Henklein P, Kopp JB. Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice[J]. Am J Physiol Endocrinol Metab, 2007, 292(1): E40-48.
[74] Xiao Y, Chen G, Richard J, Rougeau N, Li H, Seidah NG, Cohen EA. Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases[J]. Virology, 2008, 372(2): 384-397.
[75] Pauls E, Senserrich J, Clotet B, Este JA. Inhibition of HIV-1 replication by RNA interference of p53 expression[J]. J Leukoc Biol, 2006, 80(3): 659-667.
[76] Sawaya BE, Khalili K, Mercer WE, Denisova L, Amini S. Cooperative actions of HIV-1 Vpr and p53 modulate viral gene transcription[J]. J Biol Chem, 1998, 273(32): 20052-20057.
[77] Wang L, Mukherjee S, Jia F, Narayan O, Zhao LJ. Interaction of virion protein Vpr of human immunodeficiency virus type 1 with cellular transcription factor Sp1 and trans-activation of viral long terminal repeat[J]. J Biol Chem, 1995, 270(43): 25564-25569.
[78] Wang L, Mukherjee S, Narayan O, Zhao LJ. Characterization of a leucine-zipper-like domain in Vpr protein of human immunodeficiency virus type 1[J]. Gene, 1996, 178(1-2): 7-13.
[79] Kino T, Gragerov A, Slobodskaya O, Tsopanomichalou M, Chrousos GP, Pavlakis GN. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators[J]. J Virol, 2002, 76(19): 9724-9734.
[80] Shrivastav S, Kino T, Cunningham T, Ichijo T, Schubert U, Heinklein P, Chrousos GP, Kopp JB. Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor [85] and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy[J]. Mol Endocrinol, 2008, 22(2): 234-247.
[81] Agostini I, Navarro JM, Rey F, Bouhamdan M, Spire B, Vigne R, Sire J. The human immunodeficiency virus type 1 Vpr transactivator: cooperation with promoter-bound activator domains and binding to TFIIB[J]. J Mol Biol, 1996, 261(5): 599-606.
[82] Agostini I, Navarro JM, Bouhamdan M, Willetts K, Rey F, Spire B, Vigne R, Pomerantz R, Sire J. The HIV-1 Vpr co-activator induces a conformational change in TFIIB[J]. FEBS Lett, 1999, 450(3): 235-239.
[83] Varin A, Decrion AZ, Sabbah E, Quivy V, Sire J, Van Lint C, Roques BP, Aggarwal BB, Herbein G. Synthetic Vpr protein activates activator protein-1, c-Jun N-terminal kinase, and NF-kappaB and stimulates HIV-1 transcription in promonocytic cells and primary macrophages[J]. J Biol Chem, 2005, 280(52): 42557-42567.
[84] Zhu Y, Roshal M, Li F, Blackett J, Planelles V. Upregulation of survivin by HIV-1 Vpr[J]. Apoptosis, 2003, 8(1): 71-79.
[85] Muthumani K, Hwang DS, Choo AY, Mayilvahanan S, Dayes NS, Thieu KP, Weiner DB. HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro[J]. Int Immunol, 2005, 17(2): 103-116.
[86] Muthumani K, Desai BM, Hwang DS, Choo AY, Laddy DJ, Thieu KP, Rao RG, Weiner DB. HIV-1 Vpr and anti-inflammatory activity[J]. DNA Cell Biol, 2004, 23(4): 239-247.
[87] Zhao RY, Bukrinsky M, Elder RT. HIV-1 viral protein R (Vpr) & host cellular responses[J]. Indian J Med Res, 2005, 121(4): 270-286.
[88] Muthumani K, Choo AY, Hwang DS, Dayes NS, Chattergoon M, Mayilvahanan S, Thieu KP, Buckley PT, Emmanuel J, Premkumar A, Weiner DB. HIV-1 Viral protein-r (Vpr) protects against lethal superantigen challenge while maintaining homeostatic T cell levels in vivo[J]. Mol Ther, 2005, 12(5): 910-921.
[89] Majumder B, Venkatachari NJ, O'Leary S, Ayyavoo V. Infection with Vpr-positive human immunodeficiency virus type 1 impairs NK cell function indirectly through cytokine dysregulation of infected target cells[J]. J Virol, 2008, 82(14): 7189-7200.
[90] Ayyavoo V, Muthumani K, Kudchodkar S, Zhang D, Ramanathan P, Dayes NS, Kim JJ, Sin JI, Montaner LJ, Weiner DB. HIV-1 viral protein R compromises cellular immune function in vivo[J]. Int Immunol, 2002, 14(1): 13-22.
[91] Muthumani K, Hwang DS, Dayes NS, Kim JJ, Weiner DB. The HIV-1 accessory gene vpr can inhibit antigen-specific immune function[J]. DNA Cell Biol, 2002, 21(9): 689-695.
[92] Andersen JL, Planelles V. The role of Vpr in HIV-1 pathogenesis[J]. Curr HIV Res, 2005, 3(1): 43-51.
[93] Moon HS, Yang JS. Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells[J]. Mol Cells, 2006, 21(1): 7-20.
[94] Muthumani K, Choo AY, Zong WX, Madesh M, Hwang DS, Premkumar A, Thieu KP, Emmanuel J, Kumar S, Thompson CB, Weiner DB. The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1[J]. Nat Cell Biol, 2006, 8(2): 170-179.
[95] Piller SC, Jans P, Gage PW, Jans DA. Extracellular HIV-1 virus protein R causes a large inward current and cell death in cultured hippocampal neurons: implications for AIDS pathology[J]. Proc Natl Acad Sci U S A, 1998, 95(8): 4595-4600.
[96] Rom I, Deshmane SL, Mukerjee R, Khalili K, Amini S, Sawaya BE. HIV-1 Vpr deregulates calcium secretion in neural cells[J]. Brain Res, 2009, 1275: 81-86.
[97] Kitayama H, Miura Y, Ando Y, Hoshino S, Ishizaka Y, Koyanagi Y. Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction[J]. J Virol, 2008, 82(5): 2528-2542.
[98] Huang MB, Weeks O, Zhao LJ, Saltarelli M, Bond VC. Effects of extracellular human immunodeficiency virus type 1 vpr protein in primary rat cortical cell cultures[J]. J Neurovirol, 2000, 6(3): 202-220.
[99] Engler A, Stangler T, Willbold D. Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles[J]. Eur J Biochem, 2001, 268(2): 389-395.
[100] Withers-Ward ES, Jowett JB, Stewart SA, Xie YM, Garfinkel A, Shibagaki Y, Chow SA, Shah N, Hanaoka F, Sawitz DG, Armstrong RW, Souza LM, Chen IS. Human immunodeficiency virus type 1 Vpr interacts with HHR23A, a cellular protein implicated in nucleotide excision DNA repair[J]. J Virol, 1997, 71(12): 9732-9742.
[101] Wang J, Shackelford JM, Selliah N, Shivers DK, O'Neill E, Garcia JV, Muthumani K, Weiner D, Yu XF, Gabuzda D, Finkel TH. The HIV-1 Vif protein mediates degradation of Vpr and reduces Vpr-induced cell cycle arrest[J]. DNA Cell Biol, 2008, 27(5): 267-277.
[102] Basanez G, Zimmerberg J. HIV and apoptosis death and the mitochondrion[J]. J Exp Med, 2001, 193(4): F11-14.
[103] BouHamdan M, Xue Y, Baudat Y, Hu B, Sire J, Pomerantz RJ, Duan LX. Diversity of HIV-1 Vpr interactions involves usage of the WXXF motif of host cell proteins[J]. J Biol Chem, 1998, 273(14): 8009-8016.
[104] Yao XJ, Lemay J, Rougeau N, Clement M, Kurtz S, Belhumeur P, Cohen EA. Genetic selection of peptide inhibitors of human immunodeficiency virus type 1 Vpr[J]. J Biol Chem, 2002, 277(50): 48816-48826.
[1] Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma[J]. Science, 1994, 266(5192): 1865-1869.
[2] Carbone A, Cesarman E, Spina M, Gloghini A, Schulz TF. HIV-associated lymphomas and gamma-herpesviruses[J]. Blood, 2009, 113(6): 1213-1224.
[3] Schwartz RA, Micali G, Nasca MR, Scuderi L. Kaposi sarcoma: a continuing conundrum[J]. J Am Acad Dermatol, 2008, 59(2): 179-206; quiz 207-178.
[4] Decker LL, Shankar P, Khan G, Freeman RB, Dezube BJ, Lieberman J, Thorley-Lawson DA. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients[J]. J Exp Med, 1996, 184(1): 283-288.
[5] Sturzl M, Blasig C, Schreier A, Neipel F, Hohenadl C, Cornali E, Ascherl G, Esser S, Brockmeyer NH, Ekman M, Kaaya EE, Tschachler E, Biberfeld P. Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma[J]. Int J Cancer, 1997, 72(1): 68-71.
[6] Adam N, Rabe B, Suthaus J, Grotzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor[J]. J Virol, 2009, 83(10): 5117-5126.
[7] Xie J, Ajibade AO, Ye F, Kuhne K, Gao SJ. Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways[J]. Virology, 2008, 371(1): 139-154.
[8] West J, Damania B. Upregulation of the TLR3 pathway by Kaposi's sarcoma-associated herpesvirus during primary infection[J]. J Virol, 2008, 82(11): 5440-5449.
[9] Montaner S. Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma[J]. 124Cell Cycle, 2007, 6(4): 438-443.
[10] Izumiya Y, Izumiya C, Hsia D, Ellison TJ, Luciw PA, Kung HJ. NF-kappaB serves as a cellular sensor of Kaposi's sarcoma-associated herpesvirus latency and negatively regulates K-Rta by antagonizing the RBP-Jkappa coactivator[J]. J Virol, 2009, 83(9): 4435-4446.
[11] Tomlinson CC, Damania B. The K1 protein of Kaposi's sarcoma-associated herpesvirus activates the Akt signaling pathway[J]. J Virol, 2004, 78(4): 1918-1927.
[12] Guo HG, Browning P, Nicholas J, Hayward GS, Tschachler E, Jiang YW, Sadowska M, Raffeld M, Colombini S, Gallo RC, Reitz MS, Jr. Characterization of a chemokine receptor-related gene in human herpesvirus 8 and its expression in Kaposi's sarcoma[J]. Virology, 1997, 228(2): 371-378.
[13] Sodhi A, Montaner S, Gutkind JS. Viral hijacking of G-protein-coupled-receptor signalling networks[J]. Nat Rev Mol Cell Biol, 2004, 5(12): 998-1012.
[14] Cannon M, Philpott NJ, Cesarman E. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells[J]. J Virol, 2003, 77(1): 57-67.
[15] Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis I. Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture[J]. J Clin Invest, 1998, 102(8): 1469-1472.
[16] Geras-Raaka E, Varma A, Clark-Lewis I, Gershengorn MC. Kaposi's sarcoma-associated herpesvirus (KSHV) chemokine vMIP-II and human SDF-1alpha inhibit signaling by KSHV G protein-coupled receptor[J]. Biochem Biophys Res Commun, 1998, 253(3): 725-727.
[17] Geras-Raaka E, Varma A, Ho H, Clark-Lewis I, Gershengorn MC. Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor[J]. J Exp Med, 1998, 188(2): 405-408.
[18] Montaner S, Sodhi A, Ramsdell AK, Martin D, Hu J, Sawai ET, Gutkind JS. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma[J]. Cancer Res, 2006, 66(1): 168-174.
[19] Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, Sausville EA, Sawai ET, Molinolo A, Gutkind JS, Montaner S. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus Gprotein-coupled receptor[J]. Cancer Cell, 2006, 10(2): 133-143.
[20] Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y, Li Y, Ray PE, Gutkind JS. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes[J]. Cancer Cell, 2003, 3(1): 23-36.
[21] Bais C, Van Geelen A, Eroles P, Mutlu A, Chiozzini C, Dias S, Silverstein RL, Rafii S, Mesri EA. Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR[J]. Cancer Cell, 2003, 3(2): 131-143.
[22] Murakami Y, Yamagoe S, Noguchi K, Takebe Y, Takahashi N, Uehara Y, Fukazawa H. Ets-1-dependent expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus through interaction with Daxx[J]. J Biol Chem, 2006, 281(38): 28113-28121.
[23] Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling[J]. Proc Natl Acad Sci U S A, 2002, 99(21): 13571-13576.
[24] Yao R, Cooper GM. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor[J]. Science, 1995, 267(5206): 2003-2006.
[25] Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway[J]. Mol Cell, 2002, 10(1): 151-162.
[26] Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis[J]. Immunity, 1996, 5(5): 449-460.
[27] Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG, Jr. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex[J]. Genes Dev, 2004, 18(23): 2893-2904.
[28] Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways[J]. Cancer Cell, 2003, 4(2): 147-158.
[29] Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J, Michiels C.ERK activation upon hypoxia: involvement in HIF-1 activation[J]. FEBS Lett, 2000, 468(1): 53-58.
[30] Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway[J]. Proc Natl Acad Sci U S A, 1998, 95(14): 7987-7992.
[31] Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation[J]. Science, 2001, 292(5516): 468-472.
[32] Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O. Cloning of a factor required for activity of the Ah (dioxin) receptor[J]. Science, 1991, 252(5008): 954-958.
[33] Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia[J]. Proc Natl Acad Sci U S A, 1993, 90(9): 4304-4308.
[34] Acker T, Plate KH. A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology[J]. J Mol Med, 2002, 80(9): 562-575.
[35] Resnik E. beta-Catenin--one player, two games[J]. Nat Genet, 1997, 16(1): 9-11.
[36] Barker N. The canonical Wnt/beta-catenin signalling pathway[J]. Methods Mol Biol, 2008, 468: 5-15.
[37] Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. Adipogenesis and WNT signalling[J]. Trends Endocrinol Metab, 2009, 20(1): 16-24.
[38] Aulehla A, Pourquie O. Oscillating signaling pathways during embryonic development[J]. Curr Opin Cell Biol, 2008, 20(6): 632-637.
[39] Fujimuro M, Hayward SD. The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus manipulates the activity of glycogen synthase kinase-3beta[J]. J Virol, 2003, 77(14): 8019-8030.
[40] Quyn AJ, Steele RJ, Carey FA, Nathke IS. Prognostic and therapeutic implications of Apc mutations in colorectal cancer[J]. Surgeon, 2008, 6(6): 350-356.
[41] Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS, Hayward SD. A novel viral mechanism for dysregulation of beta-catenin in Kaposi's sarcoma-associated herpesvirus latency[J]. Nat Med, 2003, 9(3): 300-306.
[42] Verma SC, Lan K, Robertson E. Structure and function of latency-associated nuclearantigen[J]. Curr Top Microbiol Immunol, 2007, 312: 101-136.
[43] Ohsaki E, Suzuki T, Karayama M, Ueda K. Accumulation of LANA at nuclear matrix fraction is important for Kaposi's sarcoma-associated herpesvirus replication in latency[J]. Virus Res, 2009, 139(1): 74-84.
[44] Cheng F, Weidner-Glunde M, Varjosalo M, Rainio EM, Lehtonen A, Schulz TF, Koskinen PJ, Taipale J, Ojala PM. KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA[J]. PLoS Pathog, 2009, 5(3): e1000324.
[45] Sarek G, Kurki S, Enback J, Iotzova G, Haas J, Laakkonen P, Laiho M, Ojala PM. Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas[J]. J Clin Invest, 2007, 117(4): 1019-1028.
[46] Griffiths R, Whitehouse A. Herpesvirus saimiri episomal persistence is maintained via interaction between open reading frame 73 and the cellular chromosome-associated protein MeCP2[J]. J Virol, 2007, 81(8): 4021-4032.
[47] Lan K, Verma SC, Murakami M, Bajaj B, Kaul R, Robertson ES. Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein[J]. Proc Natl Acad Sci U S A, 2007, 104(41): 16287-16292.
[48] Fujimuro M, Hayward SD. Manipulation of glycogen-synthase kinase-3 activity in KSHV-associated cancers[J]. J Mol Med, 2004, 82(4): 223-231.
[49] An FQ, Compitello N, Horwitz E, Sramkoski M, Knudsen ES, Renne R. The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest[J]. J Biol Chem, 2005, 280(5): 3862-3874.
[50] Fakhari FD, Jeong JH, Kanan Y, Dittmer DP. The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma[J]. J Clin Invest, 2006, 116(3): 735-742.
[51] Liu J, Martin H, Shamay M, Woodard C, Tang QQ, Hayward SD. Kaposi's sarcoma-associated herpesvirus LANA protein downregulates nuclear glycogen synthase kinase 3 activity and consequently blocks differentiation[J]. J Virol, 2007, 81(9): 4722-4731.
[52] Friborg J, Jr., Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death[J]. Nature, 1999, 402(6764): 889-894.
[53] Mansouri M, Rose PP, Moses AV, Fruh K. Remodeling of endothelial adherens junctions by Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 2008, 82(19): 9615-9628.
[54] An J, Lichtenstein AK, Brent G, Rettig MB. The Kaposi sarcoma-associated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element[J]. Blood, 2002, 99(2): 649-654.
[55] An J, Sun Y, Sun R, Rettig MB. Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and JNK/AP1 pathways[J]. Oncogene, 2003, 22(22): 3371-3385.
[56] An J, Sun Y, Rettig MB. Transcriptional coactivation of c-Jun by the KSHV-encoded LANA[J]. Blood, 2004, 103(1): 222-228.
[57] Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B. ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection[J]. J Virol, 2005, 79(16): 10308-10329.
[58] Xie J, Pan H, Yoo S, Gao SJ. Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways[J]. J Virol, 2005, 79(24): 15027-15037.
[59] Naranatt PP, Akula SM, Zien CA, Krishnan HH, Chandran B. Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity[J]. J Virol, 2003, 77(2): 1524-1539.
[60] Ford PW, Bryan BA, Dyson OF, Weidner DA, Chintalgattu V, Akula SM. Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency[J]. J Gen Virol, 2006, 87(Pt 5): 1139-1144.
[61] Cohen A, Brodie C, Sarid R. An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus[J]. J Gen Virol, 2006, 87(Pt 4): 795-802.
[62] Sadler R, Wu L, Forghani B, Renne R, Zhong W, Herndier B, Ganem D. A complex translational program generates multiple novel proteins from the latently expressed kaposin (K12) locus of Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 1999, 73(7): 5722-5730.
[63] McCormick C, Ganem D. The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs[J]. Science, 2005, 307(5710): 739-741.
[64] Li H, Komatsu T, Dezube BJ, Kaye KM. The Kaposi's sarcoma-associated herpesvirus K12 transcript from a primary effusion lymphoma contains complex repeat elements, is spliced, and initiates from a novel promoter[J]. J Virol, 2002, 76(23): 11880-11888.
[65] Kliche S, Nagel W, Kremmer E, Atzler C, Ege A, Knorr T, Koszinowski U, Kolanus W, Haas J. Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1[J]. Mol Cell, 2001, 7(4): 833-843.
[66] Lanier LL. Viral immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling in cell transformation and cancer[J]. Trends Cell Biol, 2006, 16(8): 388-390.
[67] Chen SY, Lu J, Shih YC, Tsai CH. Epstein-Barr virus latent membrane protein 2A regulates c-Jun protein through extracellular signal-regulated kinase[J]. J Virol, 2002, 76(18): 9556-9561.
[68] Wang L, Dittmer DP, Tomlinson CC, Fakhari FD, Damania B. Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus[J]. Cancer Res, 2006, 66(7): 3658-3666.
[69] Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator[J]. Nature, 1998, 391(6662): 86-89.
[70] Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF. Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein[J]. J Virol, 2003, 77(17): 9346-9358.
[71] Hamza MS, Reyes RA, Izumiya Y, Wisdom R, Kung HJ, Luciw PA. ORF36 protein kinase of Kaposi's sarcoma herpesvirus activates the c-Jun N-terminal kinase signaling pathway[J]. J Biol Chem, 2004, 279(37): 38325-38330.
[72] Lee BS, Lee SH, Feng P, Chang H, Cho NH, Jung JU. Characterization of the Kaposi's sarcoma-associated herpesvirus K1 signalosome[J]. J Virol, 2005, 79(19): 12173-12184.
[73] Gonzalez CM, Wong EL, Bowser BS, Hong GK, Kenney S, Damania B. Identification and characterization of the Orf49 protein of Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 2006, 80(6): 3062-3070.
[74] Verma A, Kambhampati S, Parmar S, Platanias LC. Jak family of kinases in cancer[J]. Cancer Metastasis Rev, 2003, 22(4): 423-434.
[75] Bromberg J, Darnell JE, Jr. The role of STATs in transcriptional control and their impacton cellular function[J]. Oncogene, 2000, 19(21): 2468-2473.
[76] Darnell JE, Jr. STATs and gene regulation[J]. Science, 1997, 277(5332): 1630-1635.
[77] Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE, Jr. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions[J]. Cell, 1994, 76(5): 821-828.
[78] Burger M, Hartmann T, Burger JA, Schraufstatter I. KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway[J]. Oncogene, 2005, 24(12): 2067-2075.
[79] Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway[J]. Biochem J, 1998, 334 ( Pt 2): 297-314.
[80] Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit[J]. J Biol Chem, 1997, 272(31): 19625-19631.
[81] Wan X, Wang H, Nicholas J. Human herpesvirus 8 interleukin-6 (vIL-6) signals through gp130 but has structural and receptor-binding properties distinct from those of human IL-6[J]. J Virol, 1999, 73(10): 8268-8278.
[82] Meads MB, Medveczky PG. Kaposi's sarcoma-associated herpesvirus-encoded viral interleukin-6 is secreted and modified differently than human interleukin-6: evidence for a unique autocrine signaling mechanism[J]. J Biol Chem, 2004, 279(50): 51793-51803.
[83] Punjabi AS, Carroll PA, Chen L, Lagunoff M. Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells[J]. J Virol, 2007, 81(5): 2449-2458.
[84] Zeng Y, Zhang X, Huang Z, Cheng L, Yao S, Qin D, Chen X, Tang Q, Lv Z, Zhang L, Lu C. Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: role of JAK/STAT signaling[J]. J Virol, 2007, 81(5): 2401-2417.
[85] Brown HJ, Song MJ, Deng H, Wu TT, Cheng G, Sun R. NF-kappaB inhibits gammaherpesvirus lytic replication[J]. J Virol, 2003, 77(15): 8532-8540.
[86] Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex[J]. J Biol Chem, 2002, 277(16): 13745-13751.
[87] Field N, Low W, Daniels M, Howell S, Daviet L, Boshoff C, Collins M. KSHV vFLIP binds to IKK-gamma to activate IKK[J]. J Cell Sci, 2003, 116(Pt 18): 3721-3728.
[88] Chang MS, Lee HS, Jung EJ, Kim CW, Lee BL, Kim WH. Cell-cycle regulators, bcl-2 and NF-kappaB in Epstein-Barr virus-positive gastric carcinomas[J]. Int J Oncol, 2005, 27(5): 1265-1272.
[2] Katano H, Sata T. Human herpesvirus 8 virology, epidemiology and related diseases[J]. Jpn J Infect Dis, 2000, 53(4): 137-155.
[3] Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1)[J]. J Virol, 1998, 72(2): 1005-1012.
[4] Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, Parry JP, Peruzzi D, Edelman IS, Chang Y, Moore PS. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8)[J]. Proc Natl Acad Sci U S A, 1996, 93(25): 14862-14867.
[5] Decker LL, Shankar P, Khan G, Freeman RB, Dezube BJ, Lieberman J, Thorley-Lawson DA. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients[J]. J Exp Med, 1996, 184(1): 283-288.
[6] Sturzl M, Blasig C, Schreier A, Neipel F, Hohenadl C, Cornali E, Ascherl G, Esser S, Brockmeyer NH, Ekman M, Kaaya EE, Tschachler E, Biberfeld P. Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma[J]. Int J Cancer, 1997, 72(1): 68-71.
[7] Henry M, Uthman A, Geusau A, Rieger A, Furci L, Lazzarin A, Lusso P, Tschachler E. Infection of circulating CD34+ cells by HHV-8 in patients with Kaposi's sarcoma[J]. J Invest Dermatol, 1999, 113(4): 613-616.
[8] Mesri EA, Cesarman E, Arvanitakis L, Rafii S, Moore MA, Posnett DN, Knowles DM, Asch AS. Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus is a new transmissible virus that infects B cells[J]. J Exp Med, 1996, 183(5): 2385-2390.
[9] Lu C, Zeng Y, Huang Z, Huang L, Qian C, Tang G, Qin D. Human herpesvirus 6 activates lytic cycle replication of Kaposi's sarcoma-associatedherpesvirus[J]. Am J Pathol, 2005, 166(1): 173-183.
[10] Varthakavi V, Browning PJ, Spearman P. Human immunodeficiency virus replication in a primary effusion lymphoma cell line stimulates lytic-phase replication of Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 1999, 73(12): 10329-10338.
[11] Vieira J, O'Hearn P, Kimball L, Chandran B, Corey L. Activation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) lytic replication by human cytomegalovirus[J]. J Virol, 2001, 75(3): 1378-1386.
[12] Qin D, Zeng Y, Qian C, Huang Z, Lv Z, Cheng L, Yao S, Tang Q, Chen X, Lu C. Induction of lytic cycle replication of Kaposi's sarcoma-associated herpesvirus by herpes simplex virus type 1: involvement of IL-10 and IL-4[J]. Cell Microbiol, 2008, 10(3): 713-728.
[13] Beral V. Epidemiology of Kaposi's sarcoma[J]. Cancer Surv, 1991, 10: 5-22.
[14] Poznansky MC, Coker R, Skinner C, Hill A, Bailey S, Whitaker L, Renton A, Weber J. HIV positive patients first presenting with an AIDS defining illness: characteristics and survival[J]. BMJ, 1995, 311(6998): 156-158.
[15] Ariyoshi K, Schim van der Loeff M, Cook P, Whitby D, Corrah T, Jaffar S, Cham F, Sabally S, O'Donovan D, Weiss RA, Schulz TF, Whittle H. Kaposi's sarcoma in the Gambia, West Africa is less frequent in human immunodeficiency virus type 2 than in human immunodeficiency virus type 1 infection despite a high prevalence of human herpesvirus 8[J]. J Hum Virol, 1998, 1(3): 193-199.
[16] Delli Bovi P, Donti E, Knowles DM, 2nd, Friedman-Kien A, Luciw PA, Dina D, Dalla-Favera R, Basilico C. Presence of chromosomal abnormalities and lack of AIDS retrovirus DNA sequences in AIDS-associated Kaposi's sarcoma[J]. Cancer Res, 1986, 46(12 Pt 1): 6333-6338.
[17] Barillari G, Gendelman R, Gallo RC, Ensoli B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence[J]. Proc Natl Acad Sci U S A, 1993, 90(17): 7941-7945.
[18] Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC. Release, uptake, and effects of extracellular humanimmunodeficiency virus type 1 Tat protein on cell growth and viral transactivation[J]. J Virol, 1993, 67(1): 277-287.
[19] Watson K, Gooderham NJ, Davies DS, Edwards RJ. Interaction of the transactivating protein HIV-1 tat with sulphated polysaccharides[J]. Biochem Pharmacol, 1999, 57(7): 775-783.
[20] Frankel AD, Young JA. HIV-1: fifteen proteins and an RNA[J]. Annu Rev Biochem, 1998, 67: 1-25.
[21] Felzien LK, Woffendin C, Hottiger MO, Subbramanian RA, Cohen EA, Nabel GJ. HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator[J]. Proc Natl Acad Sci U S A, 1998, 95(9): 5281-5286.
[22] Muller B, Tessmer U, Schubert U, Krausslich HG. Human immunodeficiency virus type 1 Vpr protein is incorporated into the virion in significantly smaller amounts than gag and is phosphorylated in infected cells[J]. J Virol, 2000, 74(20): 9727-9731.
[23] Muthumani K, Kudchodkar S, Papasavvas E, Montaner LJ, Weiner DB, Ayyavoo V. HIV-1 Vpr regulates expression of beta chemokines in human primary lymphocytes and macrophages[J]. J Leukoc Biol, 2000, 68(3): 366-372.
[24] Bachand F, Yao XJ, Hrimech M, Rougeau N, Cohen EA. Incorporation of Vpr into human immunodeficiency virus type 1 requires a direct interaction with the p6 domain of the p55 gag precursor[J]. J Biol Chem, 1999, 274(13): 9083-9091.
[25] Lavallee C, Yao XJ, Ladha A, Gottlinger H, Haseltine WA, Cohen EA. Requirement of the Pr55gag precursor for incorporation of the Vpr product into human immunodeficiency virus type 1 viral particles[J]. J Virol, 1994, 68(3): 1926-1934.
[26] Sawaya BE, Khalili K, Gordon J, Taube R, Amini S. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome[J]. J Biol Chem, 2000, 275(45): 35209-35214.
[27] Chang F, Re F, Sebastian S, Sazer S, Luban J. HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes[J]. Mol Biol Cell, 2004, 15(4): 1793-1801.
[28] Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection[J]. Genes Dev, 1998, 12(2): 175-185.
[29] Rogel ME, Wu LI, Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection[J]. J Virol, 1995, 69(2): 882-888.
[30] Ramanathan MP, Curley E, 3rd, Su M, Chambers JA, Weiner DB. Carboxyl terminus of hVIP/mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling[J]. J Biol Chem, 2002, 277(49): 47854-47860.
[31] Jowett JB, Xie YM, Chen IS. The presence of human immunodeficiency virus type 1 Vpr correlates with a decrease in the frequency of mutations in a plasmid shuttle vector[J]. J Virol, 1999, 73(9): 7132-7137.
[32] Piller SC, Ewart GD, Jans DA, Gage PW, Cox GB. The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons[J]. J Virol, 1999, 73(5): 4230-4238.
[33] Levy DN, Refaeli Y, MacGregor RR, Weiner DB. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1[J]. Proc Natl Acad Sci U S A, 1994, 91(23): 10873-10877.
[34] Henklein P, Bruns K, Sherman MP, Tessmer U, Licha K, Kopp J, de Noronha CM, Greene WC, Wray V, Schubert U. Functional and structural characterization of synthetic HIV-1 Vpr that transduces cells, localizes to the nucleus, and induces G2 cell cycle arrest[J]. J Biol Chem, 2000, 275(41): 32016-32026.
[35] Sherman MP, Schubert U, Williams SA, de Noronha CM, Kreisberg JF, Henklein P, Greene WC. HIV-1 Vpr displays natural protein-transducing properties: implications for viral pathogenesis[J]. Virology, 2002, 302(1): 95-105.
[36] Zeng Y, Zhang X, Huang Z, Cheng L, Yao S, Qin D, Chen X, Tang Q, Lv Z, Zhang L, Lu C. Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: role of JAK/STAT signaling[J]. J Virol, 2007, 81(5): 2401-2417.
[37] Chen X, Cheng L, Jia X, Zeng Y, Yao S, Lv Z, Qin D, Fang X, Lei Y, Lu C.Human immunodeficiency virus type 1 Tat accelerates Kaposi sarcoma-associated herpesvirus Kaposin A-mediated tumorigenesis of transformed fibroblasts in vitro as well as in nude and immunocompetent mice[J]. Neoplasia, 2009, 11(12): 1272-1284.
[38] Guo J, Sartor M, Karyala S, Medvedovic M, Kann S, Puga A, Ryan P, Tomlinson CR. Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice[J]. Toxicol Appl Pharmacol, 2004, 194(1): 79-89.
[39] Aoki Y, Tosato G. HIV-1 Tat enhances Kaposi sarcoma-associated herpesvirus (KSHV) infectivity[J]. Blood, 2004, 104(3): 810-814.
[40] Krylov DM, Nasmyth K, Koonin EV. Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs[J]. Curr Biol, 2003, 13(2): 173-177.
[41] Benko Z, Liang D, Agbottah E, Hou J, Taricani L, Young PG, Bukrinsky M, Zhao RY. Antagonistic interaction of HIV-1 Vpr with Hsf-mediated cellular heat shock response and Hsp16 in fission yeast (Schizosaccharomyces pombe)[J]. Retrovirology, 2007, 4: 16.
[42] Huard S, Elder RT, Liang D, Li G, Zhao RY. Human immunodeficiency virus type 1 Vpr induces cell cycle G2 arrest through Srk1/MK2-mediated phosphorylation of Cdc25[J]. J Virol, 2008, 82(6): 2904-2917.
[43] Warbrick E, Fantes PA. A conserved eukaryotic cell cycle control[J]. Bioessays, 1988, 8(6): 202-204.
[44] Csikasz-Nagy A, Battogtokh D, Chen KC, Novak B, Tyson JJ. Analysis of a generic model of eukaryotic cell-cycle regulation[J]. Biophys J, 2006, 90(12): 4361-4379.
[45] Goh WC, Manel N, Emerman M. The human immunodeficiency virus Vpr protein binds Cdc25C: implications for G2 arrest[J]. Virology, 2004, 318(1): 337-349.
[46] He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity[J]. J Virol, 1995, 69(11): 6705-6711.
[47]方欣卢,曹戌,李久明,秦娣,吕志刚. HIV-I编码病毒蛋白R基因在真核细胞中的表达及其表达蛋白对KSHV溶解性周期复制的影响[J].南京医科大学学报(自然科学版), 2008, 28(9): 8.
[48] McAllister SC, Hansen SG, Messaoudi I, Nikolich-Zugich J, Moses AV. Increased efficiency of phorbol ester-induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus during S phase[J]. J Virol, 2005, 79(4): 2626-2630.
[49] Varthakavi V, Smith RM, Deng H, Sun R, Spearman P. Human immunodeficiency virus type-1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus through induction of KSHV Rta[J]. Virology, 2002, 297(2): 270-280.
[50] Merat R, Amara A, Lebbe C, de The H, Morel P, Saib A. HIV-1 infection of primary effusion lymphoma cell line triggers Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation[J]. Int J Cancer, 2002, 97(6): 791-795.
[51] Strathdee SA, Hogg RS, O'Shaughnessy MV, Montaner JS, Schechter MT. A decade of research on the natural history of HIV infection: Part 2. Cofactors[J]. Clin Invest Med, 1996, 19(2): 121-130.
[52] Aoki Y, Tosato G. Interactions between HIV-1 Tat and KSHV[J]. Curr Top Microbiol Immunol, 2007, 312: 309-326.
[53] Levy DN, Refaeli Y, Weiner DB. Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency[J]. J Virol, 1995, 69(2): 1243-1252.
[54] Ensoli B, Buonaguro L, Barillari G. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. [J].J Virol. 1993;67(4):277-287.
[55] Refaeli Y, Levy DN, Weiner DB. The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product[J]. Proc Natl Acad Sci U S A, 1995, 92(8): 3621-3625.
[56] Hogan TH, Nonnemacher MR, Krebs FC, Henderson A, Wigdahl B. HIV-1 Vpr binding to HIV-1 LTR C/EBP cis-acting elements and adjacent regions is sequence-specific[J]. Biomed Pharmacother, 2003, 57(1): 41-48.
[57] Wang L, Mukherjee S, Jia F, Narayan O, Zhao LJ. Interaction of virion protein Vpr of human immunodeficiency virus type 1 with cellulartranscription factor Sp1 and trans-activation of viral long terminal repeat[J]. J Biol Chem, 1995, 270(43): 25564-25569.
[58] Lan K, Kuppers DA, Verma SC, Robertson ES. Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency[J]. J Virol, 2004, 78(12): 6585-6594.
[59] Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll-like receptor signaling controls reactivation of KSHV from latency[J]. Proc Natl Acad Sci U S A, 2009, 106(28): 11725-11730.
[60] Vieira J, O'Hearn PM. Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression[J]. Virology, 2004, 325(2): 225-240.
[61] Chang J, Renne R, Dittmer D, Ganem D. Inflammatory cytokines and the reactivation of Kaposi's sarcoma-associated herpesvirus lytic replication[J]. Virology, 2000, 266(1): 17-25.
[62] Zoeteweij JP, Rinderknecht AS, Davis DA, Yarchoan R, Blauvelt A. Minimal reactivation of Kaposi's sarcoma-associated herpesvirus by corticosteroids in latently infected B cell lines[J]. J Med Virol, 2002, 66(3): 378-383.
[63] Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G. A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus[J]. Proc Natl Acad Sci U S A, 1998, 95(18): 10866-10871.
[64] Martin D, Gutkind JS. Human tumor-associated viruses and new insights into the molecular mechanisms of cancer[J]. Oncogene, 2008, 27 Suppl 2: S31-42.
[65] Lu F, Day L, Gao SJ, Lieberman PM. Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi's sarcoma-associated herpesvirus lytic transcription[J]. J Virol, 2006, 80(11): 5273-5282.
[66] Lan K, Kuppers DA, Robertson ES. Kaposi's sarcoma-associated herpesvirus reactivation is regulated by interaction of latency-associated nuclear antigen with recombination signal sequence-binding protein Jkappa, the major downstream effector of the Notch signaling pathway[J]. J Virol, 2005, 79(6): 3468-3478.
[67] Renne R, Zhong W, Herndier B, McGrath M, Abbey N, Kedes D, Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus8) in culture[J]. Nat Med, 1996, 2(3): 342-346.
[68] Li Z, Tan F, Thiele CJ. Inactivation of glycogen synthase kinase-3beta contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells[J]. Mol Cancer Ther, 2007, 6(12 Pt 1): 3113-3121.
[69] Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development[J]. Proc Natl Acad Sci U S A, 1996, 93(16): 8455-8459.
[70] Brown HJ, Song MJ, Deng H, Wu TT, Cheng G, Sun R. NF-kappaB inhibits gammaherpesvirus lytic replication[J]. J Virol, 2003, 77(15): 8532-8540.
[71] Keller SA, Schattner EJ, Cesarman E. Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells[J]. Blood, 2000, 96(7): 2537-2542.
[72] Grossmann C, Ganem D. Effects of NFkappaB activation on KSHV latency and lytic reactivation are complex and context-dependent[J]. Virology, 2008, 375(1): 94-102.
[73] Qian LW, Xie J, Ye F, Gao SJ. Kaposi's sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases[J]. J Virol, 2007, 81(13): 7001-7010.
[74] Cohen A, Brodie C, Sarid R. An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus[J]. J Gen Virol, 2006, 87(Pt 4): 795-802.
[75] Ford PW, Bryan BA, Dyson OF, Weidner DA, Chintalgattu V, Akula SM. Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency[J]. J Gen Virol, 2006, 87(Pt 5): 1139-1144.
[76] Fujimuro M, Nakaso K, Nakashima K, Sadanari H, Hisanori I, Teishikata Y, Hayward SD, Yokosawa H. Multiplex PCR-based DNA array for simultaneous detection of three human herpesviruses, EVB, CMV and KSHV[J]. Exp Mol Pathol, 2006, 80(2): 124-131.
[77] Montaner S. Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma[J]. Cell Cycle, 2007, 6(4): 438-443.
[78] Bryan MA, Socha MT, Tomlinson DJ. Supplementing intensively grazed late-gestation and early-lactation dairy cattle with chromium[J]. J Dairy Sci,2004, 87(12): 4269-4277.
[79] Hackett ML, Yang M, Anderson CS, Horrocks JA, House A. Pharmaceutical interventions for emotionalism after stroke[J]. Cochrane Database Syst Rev, 2: CD003690.
[80] Mingyan Y, Xinyong L, De Clercq E. NF-kappaB: the inducible factors of HIV-1 transcription and their inhibitors[J]. Mini Rev Med Chem, 2009, 9(1): 60-69.
[81] Dabrowska A, Kim N, Aldovini A. Tat-induced FOXO3a is a key mediator of apoptosis in HIV-1-infected human CD4+ T lymphocytes[J]. J Immunol, 2008, 181(12): 8460-8477.
[82] Witte V, Laffert B, Gintschel P, Krautkramer E, Blume K, Fackler OT, Baur AS. Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta raft recruitment leading to activation of ERK1/2 but not NF kappa B[J]. J Immunol, 2008, 181(12): 8425-8432.
[83] Cui M, Huang Y, Zhao Y, Zheng J. Transcription factor FOXO3a mediates apoptosis in HIV-1-infected macrophages[J]. J Immunol, 2008, 180(2): 898-906.
[84] Sgarbanti M, Arguello M, tenOever BR, Battistini A, Lin R, Hiscott J. A requirement for NF-kappaB induction in the production of replication-competent HHV-8 virions[J]. Oncogene, 2004, 23(34): 5770-5780.
[85] Albert F, Anderson SG, Anderson GA, Betts SM, Gibson DJ, Hagmann CA, Hall J, Johnson MS, Messerly MJ, Semenov VA, Shverdin MY, Tremaine AM, Hartemann FV, Siders CW, McNabb DP, Barty CP. Isotope-specific detection of low-density materials with laser-based monoenergetic gamma-rays[J]. Opt Lett, 35(3): 354-356.
[1] Tungaturthi PK, Sawaya BE, Ayyavoo V, Murali R, Srinivasan A. HIV-1 Vpr: genetic diversity and functional features from the perspective of structure[J]. DNA Cell Biol, 2004, 23(4): 207-222.
[2] Anderson JL, Hope TJ. HIV accessory proteins and surviving the host cell[J]. Curr HIV/AIDS Rep, 2004, 1(1): 47-53.
[3] Felzien LK, Woffendin C, Hottiger MO, Subbramanian RA, Cohen EA, Nabel GJ. HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator[J]. Proc Natl Acad Sci U S A, 1998, 95(9): 5281-5286.
[4] Muller B, Tessmer U, Schubert U, Krausslich HG. Human immunodeficiency virus type 1 Vpr protein is incorporated into the virion in significantly smaller amounts than gag and is phosphorylated in infected cells[J]. J Virol, 2000, 74(20): 9727-9731.
[5] Muthumani K, Kudchodkar S, Papasavvas E, Montaner LJ, Weiner DB, Ayyavoo V. HIV-1 Vpr regulates expression of beta chemokines in human primary lymphocytes and macrophages[J]. J Leukoc Biol, 2000, 68(3): 366-372.
[6] Bachand F, Yao XJ, Hrimech M, Rougeau N, Cohen EA. Incorporation of Vpr into human immunodeficiency virus type 1 requires a direct interaction with the p6 domain of the p55 gag precursor[J]. J Biol Chem, 1999, 274(13): 9083-9091.
[7] Lavallee C, Yao XJ, Ladha A, Gottlinger H, Haseltine WA, Cohen EA. Requirement of the Pr55gag precursor for incorporation of the Vpr product into human immunodeficiency virus type 1 viral particles[J]. J Virol, 1994, 68(3): 1926-1934.
[8] Sawaya BE, Khalili K, Gordon J, Taube R, Amini S. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome[J]. J Biol Chem, 2000, 275(45): 35209-35214.
[9] Chang F, Re F, Sebastian S, Sazer S, Luban J. HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes[J]. Mol Biol Cell, 2004, 15(4): 1793-1801.
[10] Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection[J]. Genes Dev, 1998, 12(2): 175-185.
[11] Rogel ME, Wu LI, Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection[J]. J Virol, 1995, 69(2): 882-888.
[12] Ramanathan MP, Curley E, 3rd, Su M, Chambers JA, Weiner DB. Carboxyl terminus of hVIP/mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling[J]. J Biol Chem, 2002, 277(49): 47854-47860.
[13] Jowett JB, Xie YM, Chen IS. The presence of human immunodeficiency virus type 1 Vpr correlates with a decrease in the frequency of mutations in a plasmid shuttle vector[J]. J Virol, 1999, 73(9): 7132-7137.
[14] Piller SC, Ewart GD, Jans DA, Gage PW, Cox GB. The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons[J]. J Virol, 1999, 73(5): 4230-4238.
[15] Somasundaran M, Sharkey M, Brichacek B, Luzuriaga K, Emerman M, Sullivan JL, Stevenson M. Evidence for a cytopathogenicity determinant in HIV-1 Vpr[J]. Proc Natl Acad Sci U S A, 2002, 99(14): 9503-9508.
[16] Roumier T, Vieira HL, Castedo M, Ferri KF, Boya P, Andreau K, Druillennec S, Joza N, Penninger JM, Roques B, Kroemer G. The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway[J]. Cell Death Differ, 2002, 9(11): 1212-1219.
[17] Srinivasan A, Ayyavoo V, Mahalingam S, Kannan A, Boyd A, Datta D, KalyanaramanVS, Cristillo A, Collman RG, Morellet N, Sawaya BE, Murali R. A comprehensive analysis of the naturally occurring polymorphisms in HIV-1 Vpr: potential impact on CTL epitopes[J]. Virol J, 2008, 5: 99.
[18] Jenkins Y, McEntee M, Weis K, Greene WC. Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways[J]. J Cell Biol, 1998, 143(4): 875-885.
[19] Le Rouzic E, Mousnier A, Rustum C, Stutz F, Hallberg E, Dargemont C, Benichou S. Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1[J]. J Biol Chem, 2002, 277(47): 45091-45098.
[20] Schang LM. The cell cycle, cyclin-dependent kinases, and viral infections: new horizons and unexpected connections[J]. Prog Cell Cycle Res, 2003, 5: 103-124.
[21] Suzuki T, Yamamoto N, Nonaka M, Hashimoto Y, Matsuda G, Takeshima SN, Matsuyama M, Igarashi T, Miura T, Tanaka R, Kato S, Aida Y. Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr-Importin alpha interactions as a novel HIV-1 therapy[J]. Biochem Biophys Res Commun, 2009, 380(4): 838-843.
[22] Gallay P, Stitt V, Mundy C, Oettinger M, Trono D. Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import[J]. J Virol, 1996, 70(2): 1027-1032.
[23] Gallay P, Hope T, Chin D, Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway[J]. Proc Natl Acad Sci U S A, 1997, 94(18): 9825-9830.
[24] Nitahara-Kasahara Y, Kamata M, Yamamoto T, Zhang X, Miyamoto Y, Muneta K, Iijima S, Yoneda Y, Tsunetsugu-Yokota Y, Aida Y. Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages[J]. J Virol, 2007, 81(10): 5284-5293.
[25] Le Rouzic E, Benichou S. The Vpr protein from HIV-1: distinct roles along the viral life cycle[J]. Retrovirology, 2005, 2: 11.
[26] Zeitler B, Weis K. The FG-repeat asymmetry of the nuclear pore complex is dispensable for bulk nucleocytoplasmic transport in vivo[J]. J Cell Biol, 2004, 167(4): 583-590.
[27] de Noronha CM, Sherman MP, Lin HW, Cavrois MV, Moir RD, Goldman RD, Greene WC. Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr[J]. Science, 2001, 294(5544): 1105-1108.
[28] Basavapathruni A, Anderson KS. Reverse transcription of the HIV-1 pandemic[J].FASEB J, 2007, 21(14): 3795-3808.
[29] Li Y, Zhang Z, Wakefield JK, Kang SM, Morrow CD. Nucleotide substitutions within U5 are critical for efficient reverse transcription of human immunodeficiency virus type 1 with a primer binding site complementary to tRNA(His)[J]. J Virol, 1997, 71(9): 6315-6322.
[30] Gao L, Balakrishnan M, Roques BP, Bambara RA. Insights into the multiple roles of pausing in HIV-1 reverse transcriptase-promoted strand transfers[J]. J Biol Chem, 2007, 282(9): 6222-6231.
[31] Sun Y, Pinchuk LM, Agy MB, Clark EA. Nuclear import of HIV-1 DNA in resting CD4+ T cells requires a cyclosporin A-sensitive pathway[J]. J Immunol, 1997, 158(1): 512-517.
[32] Chen R, Le Rouzic E, Kearney JA, Mansky LM, Benichou S. Vpr-mediated incorporation of UNG2 into HIV-1 particles is required to modulate the virus mutation rate and for replication in macrophages[J]. J Biol Chem, 2004, 279(27): 28419-28425.
[33] Mansky LM, Preveral S, Selig L, Benarous R, Benichou S. The interaction of vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 In vivo mutation rate[J]. J Virol, 2000, 74(15): 7039-7047.
[34] Chen R, Wang H, Mansky LM. Roles of uracil-DNA glycosylase and dUTPase in virus replication[J]. J Gen Virol, 2002, 83(Pt 10): 2339-2345.
[35] Berkhout B, de Ronde A. APOBEC3G versus reverse transcriptase in the generation of HIV-1 drug-resistance mutations[J]. AIDS, 2004, 18(13): 1861-1863.
[36] Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, Wei X, Jiang C, Kirchherr JL, Gao F, Anderson JA, Ping LH, Swanstrom R, Tomaras GD, Blattner WA, Goepfert PA, Kilby JM, Saag MS, Delwart EL, Busch MP, Cohen MS, Montefiori DC, Haynes BF, Gaschen B, Athreya GS, Lee HY, Wood N, Seoighe C, Perelson AS, Bhattacharya T, Korber BT, Hahn BH, Shaw GM. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection[J]. Proc Natl Acad Sci U S A, 2008, 105(21): 7552-7557.
[37] Priet S, Navarro JM, Gros N, Querat G, Sire J. Functional role of HIV-1 virion-associated uracil DNA glycosylase 2 in the correction of G:U mispairs to G:C pairs[J]. J Biol Chem, 2003, 278(7): 4566-4571.
[38] Mansky LM. The mutation rate of human immunodeficiency virus type 1 is influenced by the vpr gene[J]. Virology, 1996, 222(2): 391-400.
[39] Bouhamdan M, Benichou S, Rey F, Navarro JM, Agostini I, Spire B, Camonis J, Slupphaug G, Vigne R, Benarous R, Sire J. Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme[J]. J Virol, 1996, 70(2): 697-704.
[40] Belzile JP, Duisit G, Rougeau N, Mercier J, Finzi A, Cohen EA. HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase[J]. PLoS Pathog, 2007, 3(7): e85.
[41] Elder RT, Yu M, Chen M, Zhu X, Yanagida M, Zhao Y. HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25[J]. Virology, 2001, 287(2): 359-370.
[42] Goh WC, Rogel ME, Kinsey CM, Michael SF, Fultz PN, Nowak MA, Hahn BH, Emerman M. HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo[J]. Nat Med, 1998, 4(1): 65-71.
[43] Krylov DM, Nasmyth K, Koonin EV. Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs[J]. Curr Biol, 2003, 13(2): 173-177.
[44] Benko Z, Liang D, Agbottah E, Hou J, Taricani L, Young PG, Bukrinsky M, Zhao RY. Antagonistic interaction of HIV-1 Vpr with Hsf-mediated cellular heat shock response and Hsp16 in fission yeast (Schizosaccharomyces pombe)[J]. Retrovirology, 2007, 4: 16.
[45] Huard S, Elder RT, Liang D, Li G, Zhao RY. Human immunodeficiency virus type 1 Vpr induces cell cycle G2 arrest through Srk1/MK2-mediated phosphorylation of Cdc25[J]. J Virol, 2008, 82(6): 2904-2917.
[46] Warbrick E, Fantes PA. A conserved eukaryotic cell cycle control[J]. Bioessays, 1988, 8(6): 202-204.
[47] Csikasz-Nagy A, Battogtokh D, Chen KC, Novak B, Tyson JJ. Analysis of a generic model of eukaryotic cell-cycle regulation[J]. Biophys J, 2006, 90(12): 4361-4379.
[48] Goh WC, Manel N, Emerman M. The human immunodeficiency virus Vpr protein binds Cdc25C: implications for G2 arrest[J]. Virology, 2004, 318(1): 337-349.
[49] He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity[J]. J Virol, 1995, 69(11): 6705-6711.
[50] Kino T, Gragerov A, Valentin A, Tsopanomihalou M, Ilyina-Gragerova G, Erwin-CohenR, Chrousos GP, Pavlakis GN. Vpr protein of human immunodeficiency virus type 1 binds to 14-3-3 proteins and facilitates complex formation with Cdc25C: implications for cell cycle arrest[J]. J Virol, 2005, 79(5): 2780-2787.
[51] Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals[J]. Genes Dev, 1998, 12(19): 2973-2983.
[52] Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, Washburn MP, Skowronski J. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle[J]. Proc Natl Acad Sci U S A, 2007, 104(28): 11778-11783.
[53] Wen X, Duus KM, Friedrich TD, de Noronha CM. The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor[J]. J Biol Chem, 2007, 282(37): 27046-27057.
[54] Higa LA, Zhang H. Stealing the spotlight: CUL4-DDB1 ubiquitin ligase docks WD40-repeat proteins to destroy[J]. Cell Div, 2007, 2: 5.
[55] Jin J, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1[J]. Mol Cell, 2006, 23(5): 709-721.
[56] Rialland M, Sola F, Santocanale C. Essential role of human CDT1 in DNA replication and chromatin licensing[J]. J Cell Sci, 2002, 115(Pt 7): 1435-1440.
[57] Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis[J]. Annu Rev Cell Dev Biol, 1999, 15: 269-290.
[58] Green DR. Apoptotic pathways: paper wraps stone blunts scissors[J]. Cell, 2000, 102(1): 1-4.
[59] Andersen JL, Le Rouzic E, Planelles V. HIV-1 Vpr: mechanisms of G2 arrest and apoptosis[J]. Exp Mol Pathol, 2008, 85(1): 2-10.
[60] Chang LJ, Chen CH, Urlacher V, Lee TZ. Differential apoptosis effects of primate lentiviral Vpr and Vpx in mammalian cells[J]. J Biomed Sci, 2000, 7(4): 322-333.
[61] Conti L, Matarrese P, Varano B, Gauzzi MC, Sato A, Malorni W, Belardelli F, Gessani S. Dual role of the HIV-1 vpr protein in the modulation of the apoptotic response of T cells[J]. J Immunol, 2000, 165(6): 3293-3300.
[62] Stewart SA, Poon B, Jowett JB, Xie Y, Chen IS. Lentiviral delivery of HIV-1 Vpr protein induces apoptosis in transformed cells[J]. Proc Natl Acad Sci U S A, 1999, 96(21): 12039-12043.
[63] Yedavalli VS, Shih HM, Chiang YP, Lu CY, Chang LY, Chen MY, Chuang CY, Dayton AI, Jeang KT, Huang LM. Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1[J]. J Virol, 2005, 79(21): 13735-13746.
[64] Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, Costantini P, Druillennec S, Hoebeke J, Briand JP, Irinopoulou T, Daugas E, Susin SA, Cointe D, Xie ZH, Reed JC, Roques BP, Kroemer G. The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore[J]. J Exp Med, 2000, 191(1): 33-46.
[65] Jacotot E, Ferri KF, El Hamel C, Brenner C, Druillennec S, Hoebeke J, Rustin P, Metivier D, Lenoir C, Geuskens M, Vieira HL, Loeffler M, Belzacq AS, Briand JP, Zamzami N, Edelman L, Xie ZH, Reed JC, Roques BP, Kroemer G. Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2[J]. J Exp Med, 2001, 193(4): 509-519.
[66] Kim HE, Du F, Fang M, Wang X. Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1[J]. Proc Natl Acad Sci U S A, 2005, 102(49): 17545-17550.
[67] Muthumani K, Hwang DS, Desai BM, Zhang D, Dayes N, Green DR, Weiner DB. HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells[J]. J Biol Chem, 2002, 277(40): 37820-37831.
[68] Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC. Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP[J]. J Biol Chem, 2003, 278(10): 8091-8098.
[69] Arunagiri C, Macreadie I, Hewish D, Azad A. A C-terminal domain of HIV-1 accessory protein Vpr is involved in penetration, mitochondrial dysfunction and apoptosis of human CD4+ lymphocytes[J]. Apoptosis, 1997, 2(1): 69-76.
[70] Zhu Y, Gelbard HA, Roshal M, Pursell S, Jamieson BD, Planelles V. Comparison of cell cycle arrest, transactivation, and apoptosis induced by the simian immunodeficiency virus SIVagm and human immunodeficiency virus type 1 vpr genes[J]. J Virol, 2001, 75(8): 3791-3801.
[71] Kino T, Chrousos GP. Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?[J]. Ann N Y Acad Sci, 2004, 1024: 153-167.
[72] Poon B, Chang MA, Chen IS. Vpr is required for efficient Nef expression fromunintegrated human immunodeficiency virus type 1 DNA[J]. J Virol, 2007, 81(19): 10515-10523.
[73] Balasubramanyam A, Mersmann H, Jahoor F, Phillips TM, Sekhar RV, Schubert U, Brar B, Iyer D, Smith EO, Takahashi H, Lu H, Anderson P, Kino T, Henklein P, Kopp JB. Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice[J]. Am J Physiol Endocrinol Metab, 2007, 292(1): E40-48.
[74] Xiao Y, Chen G, Richard J, Rougeau N, Li H, Seidah NG, Cohen EA. Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases[J]. Virology, 2008, 372(2): 384-397.
[75] Pauls E, Senserrich J, Clotet B, Este JA. Inhibition of HIV-1 replication by RNA interference of p53 expression[J]. J Leukoc Biol, 2006, 80(3): 659-667.
[76] Sawaya BE, Khalili K, Mercer WE, Denisova L, Amini S. Cooperative actions of HIV-1 Vpr and p53 modulate viral gene transcription[J]. J Biol Chem, 1998, 273(32): 20052-20057.
[77] Wang L, Mukherjee S, Jia F, Narayan O, Zhao LJ. Interaction of virion protein Vpr of human immunodeficiency virus type 1 with cellular transcription factor Sp1 and trans-activation of viral long terminal repeat[J]. J Biol Chem, 1995, 270(43): 25564-25569.
[78] Wang L, Mukherjee S, Narayan O, Zhao LJ. Characterization of a leucine-zipper-like domain in Vpr protein of human immunodeficiency virus type 1[J]. Gene, 1996, 178(1-2): 7-13.
[79] Kino T, Gragerov A, Slobodskaya O, Tsopanomichalou M, Chrousos GP, Pavlakis GN. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators[J]. J Virol, 2002, 76(19): 9724-9734.
[80] Shrivastav S, Kino T, Cunningham T, Ichijo T, Schubert U, Heinklein P, Chrousos GP, Kopp JB. Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor [85] and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy[J]. Mol Endocrinol, 2008, 22(2): 234-247.
[81] Agostini I, Navarro JM, Rey F, Bouhamdan M, Spire B, Vigne R, Sire J. The human immunodeficiency virus type 1 Vpr transactivator: cooperation with promoter-bound activator domains and binding to TFIIB[J]. J Mol Biol, 1996, 261(5): 599-606.
[82] Agostini I, Navarro JM, Bouhamdan M, Willetts K, Rey F, Spire B, Vigne R, Pomerantz R, Sire J. The HIV-1 Vpr co-activator induces a conformational change in TFIIB[J]. FEBS Lett, 1999, 450(3): 235-239.
[83] Varin A, Decrion AZ, Sabbah E, Quivy V, Sire J, Van Lint C, Roques BP, Aggarwal BB, Herbein G. Synthetic Vpr protein activates activator protein-1, c-Jun N-terminal kinase, and NF-kappaB and stimulates HIV-1 transcription in promonocytic cells and primary macrophages[J]. J Biol Chem, 2005, 280(52): 42557-42567.
[84] Zhu Y, Roshal M, Li F, Blackett J, Planelles V. Upregulation of survivin by HIV-1 Vpr[J]. Apoptosis, 2003, 8(1): 71-79.
[85] Muthumani K, Hwang DS, Choo AY, Mayilvahanan S, Dayes NS, Thieu KP, Weiner DB. HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro[J]. Int Immunol, 2005, 17(2): 103-116.
[86] Muthumani K, Desai BM, Hwang DS, Choo AY, Laddy DJ, Thieu KP, Rao RG, Weiner DB. HIV-1 Vpr and anti-inflammatory activity[J]. DNA Cell Biol, 2004, 23(4): 239-247.
[87] Zhao RY, Bukrinsky M, Elder RT. HIV-1 viral protein R (Vpr) & host cellular responses[J]. Indian J Med Res, 2005, 121(4): 270-286.
[88] Muthumani K, Choo AY, Hwang DS, Dayes NS, Chattergoon M, Mayilvahanan S, Thieu KP, Buckley PT, Emmanuel J, Premkumar A, Weiner DB. HIV-1 Viral protein-r (Vpr) protects against lethal superantigen challenge while maintaining homeostatic T cell levels in vivo[J]. Mol Ther, 2005, 12(5): 910-921.
[89] Majumder B, Venkatachari NJ, O'Leary S, Ayyavoo V. Infection with Vpr-positive human immunodeficiency virus type 1 impairs NK cell function indirectly through cytokine dysregulation of infected target cells[J]. J Virol, 2008, 82(14): 7189-7200.
[90] Ayyavoo V, Muthumani K, Kudchodkar S, Zhang D, Ramanathan P, Dayes NS, Kim JJ, Sin JI, Montaner LJ, Weiner DB. HIV-1 viral protein R compromises cellular immune function in vivo[J]. Int Immunol, 2002, 14(1): 13-22.
[91] Muthumani K, Hwang DS, Dayes NS, Kim JJ, Weiner DB. The HIV-1 accessory gene vpr can inhibit antigen-specific immune function[J]. DNA Cell Biol, 2002, 21(9): 689-695.
[92] Andersen JL, Planelles V. The role of Vpr in HIV-1 pathogenesis[J]. Curr HIV Res, 2005, 3(1): 43-51.
[93] Moon HS, Yang JS. Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells[J]. Mol Cells, 2006, 21(1): 7-20.
[94] Muthumani K, Choo AY, Zong WX, Madesh M, Hwang DS, Premkumar A, Thieu KP, Emmanuel J, Kumar S, Thompson CB, Weiner DB. The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1[J]. Nat Cell Biol, 2006, 8(2): 170-179.
[95] Piller SC, Jans P, Gage PW, Jans DA. Extracellular HIV-1 virus protein R causes a large inward current and cell death in cultured hippocampal neurons: implications for AIDS pathology[J]. Proc Natl Acad Sci U S A, 1998, 95(8): 4595-4600.
[96] Rom I, Deshmane SL, Mukerjee R, Khalili K, Amini S, Sawaya BE. HIV-1 Vpr deregulates calcium secretion in neural cells[J]. Brain Res, 2009, 1275: 81-86.
[97] Kitayama H, Miura Y, Ando Y, Hoshino S, Ishizaka Y, Koyanagi Y. Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction[J]. J Virol, 2008, 82(5): 2528-2542.
[98] Huang MB, Weeks O, Zhao LJ, Saltarelli M, Bond VC. Effects of extracellular human immunodeficiency virus type 1 vpr protein in primary rat cortical cell cultures[J]. J Neurovirol, 2000, 6(3): 202-220.
[99] Engler A, Stangler T, Willbold D. Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles[J]. Eur J Biochem, 2001, 268(2): 389-395.
[100] Withers-Ward ES, Jowett JB, Stewart SA, Xie YM, Garfinkel A, Shibagaki Y, Chow SA, Shah N, Hanaoka F, Sawitz DG, Armstrong RW, Souza LM, Chen IS. Human immunodeficiency virus type 1 Vpr interacts with HHR23A, a cellular protein implicated in nucleotide excision DNA repair[J]. J Virol, 1997, 71(12): 9732-9742.
[101] Wang J, Shackelford JM, Selliah N, Shivers DK, O'Neill E, Garcia JV, Muthumani K, Weiner D, Yu XF, Gabuzda D, Finkel TH. The HIV-1 Vif protein mediates degradation of Vpr and reduces Vpr-induced cell cycle arrest[J]. DNA Cell Biol, 2008, 27(5): 267-277.
[102] Basanez G, Zimmerberg J. HIV and apoptosis death and the mitochondrion[J]. J Exp Med, 2001, 193(4): F11-14.
[103] BouHamdan M, Xue Y, Baudat Y, Hu B, Sire J, Pomerantz RJ, Duan LX. Diversity of HIV-1 Vpr interactions involves usage of the WXXF motif of host cell proteins[J]. J Biol Chem, 1998, 273(14): 8009-8016.
[104] Yao XJ, Lemay J, Rougeau N, Clement M, Kurtz S, Belhumeur P, Cohen EA. Genetic selection of peptide inhibitors of human immunodeficiency virus type 1 Vpr[J]. J Biol Chem, 2002, 277(50): 48816-48826.
[1] Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma[J]. Science, 1994, 266(5192): 1865-1869.
[2] Carbone A, Cesarman E, Spina M, Gloghini A, Schulz TF. HIV-associated lymphomas and gamma-herpesviruses[J]. Blood, 2009, 113(6): 1213-1224.
[3] Schwartz RA, Micali G, Nasca MR, Scuderi L. Kaposi sarcoma: a continuing conundrum[J]. J Am Acad Dermatol, 2008, 59(2): 179-206; quiz 207-178.
[4] Decker LL, Shankar P, Khan G, Freeman RB, Dezube BJ, Lieberman J, Thorley-Lawson DA. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients[J]. J Exp Med, 1996, 184(1): 283-288.
[5] Sturzl M, Blasig C, Schreier A, Neipel F, Hohenadl C, Cornali E, Ascherl G, Esser S, Brockmeyer NH, Ekman M, Kaaya EE, Tschachler E, Biberfeld P. Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma[J]. Int J Cancer, 1997, 72(1): 68-71.
[6] Adam N, Rabe B, Suthaus J, Grotzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor[J]. J Virol, 2009, 83(10): 5117-5126.
[7] Xie J, Ajibade AO, Ye F, Kuhne K, Gao SJ. Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways[J]. Virology, 2008, 371(1): 139-154.
[8] West J, Damania B. Upregulation of the TLR3 pathway by Kaposi's sarcoma-associated herpesvirus during primary infection[J]. J Virol, 2008, 82(11): 5440-5449.
[9] Montaner S. Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma[J]. 124Cell Cycle, 2007, 6(4): 438-443.
[10] Izumiya Y, Izumiya C, Hsia D, Ellison TJ, Luciw PA, Kung HJ. NF-kappaB serves as a cellular sensor of Kaposi's sarcoma-associated herpesvirus latency and negatively regulates K-Rta by antagonizing the RBP-Jkappa coactivator[J]. J Virol, 2009, 83(9): 4435-4446.
[11] Tomlinson CC, Damania B. The K1 protein of Kaposi's sarcoma-associated herpesvirus activates the Akt signaling pathway[J]. J Virol, 2004, 78(4): 1918-1927.
[12] Guo HG, Browning P, Nicholas J, Hayward GS, Tschachler E, Jiang YW, Sadowska M, Raffeld M, Colombini S, Gallo RC, Reitz MS, Jr. Characterization of a chemokine receptor-related gene in human herpesvirus 8 and its expression in Kaposi's sarcoma[J]. Virology, 1997, 228(2): 371-378.
[13] Sodhi A, Montaner S, Gutkind JS. Viral hijacking of G-protein-coupled-receptor signalling networks[J]. Nat Rev Mol Cell Biol, 2004, 5(12): 998-1012.
[14] Cannon M, Philpott NJ, Cesarman E. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells[J]. J Virol, 2003, 77(1): 57-67.
[15] Gershengorn MC, Geras-Raaka E, Varma A, Clark-Lewis I. Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture[J]. J Clin Invest, 1998, 102(8): 1469-1472.
[16] Geras-Raaka E, Varma A, Clark-Lewis I, Gershengorn MC. Kaposi's sarcoma-associated herpesvirus (KSHV) chemokine vMIP-II and human SDF-1alpha inhibit signaling by KSHV G protein-coupled receptor[J]. Biochem Biophys Res Commun, 1998, 253(3): 725-727.
[17] Geras-Raaka E, Varma A, Ho H, Clark-Lewis I, Gershengorn MC. Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor[J]. J Exp Med, 1998, 188(2): 405-408.
[18] Montaner S, Sodhi A, Ramsdell AK, Martin D, Hu J, Sawai ET, Gutkind JS. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma[J]. Cancer Res, 2006, 66(1): 168-174.
[19] Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, Sausville EA, Sawai ET, Molinolo A, Gutkind JS, Montaner S. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus Gprotein-coupled receptor[J]. Cancer Cell, 2006, 10(2): 133-143.
[20] Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y, Li Y, Ray PE, Gutkind JS. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes[J]. Cancer Cell, 2003, 3(1): 23-36.
[21] Bais C, Van Geelen A, Eroles P, Mutlu A, Chiozzini C, Dias S, Silverstein RL, Rafii S, Mesri EA. Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR[J]. Cancer Cell, 2003, 3(2): 131-143.
[22] Murakami Y, Yamagoe S, Noguchi K, Takebe Y, Takahashi N, Uehara Y, Fukazawa H. Ets-1-dependent expression of vascular endothelial growth factor receptors is activated by latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus through interaction with Daxx[J]. J Biol Chem, 2006, 281(38): 28113-28121.
[23] Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling[J]. Proc Natl Acad Sci U S A, 2002, 99(21): 13571-13576.
[24] Yao R, Cooper GM. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor[J]. Science, 1995, 267(5206): 2003-2006.
[25] Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway[J]. Mol Cell, 2002, 10(1): 151-162.
[26] Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis[J]. Immunity, 1996, 5(5): 449-460.
[27] Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG, Jr. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex[J]. Genes Dev, 2004, 18(23): 2893-2904.
[28] Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways[J]. Cancer Cell, 2003, 4(2): 147-158.
[29] Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J, Michiels C.ERK activation upon hypoxia: involvement in HIF-1 activation[J]. FEBS Lett, 2000, 468(1): 53-58.
[30] Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway[J]. Proc Natl Acad Sci U S A, 1998, 95(14): 7987-7992.
[31] Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation[J]. Science, 2001, 292(5516): 468-472.
[32] Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O. Cloning of a factor required for activity of the Ah (dioxin) receptor[J]. Science, 1991, 252(5008): 954-958.
[33] Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia[J]. Proc Natl Acad Sci U S A, 1993, 90(9): 4304-4308.
[34] Acker T, Plate KH. A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology[J]. J Mol Med, 2002, 80(9): 562-575.
[35] Resnik E. beta-Catenin--one player, two games[J]. Nat Genet, 1997, 16(1): 9-11.
[36] Barker N. The canonical Wnt/beta-catenin signalling pathway[J]. Methods Mol Biol, 2008, 468: 5-15.
[37] Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. Adipogenesis and WNT signalling[J]. Trends Endocrinol Metab, 2009, 20(1): 16-24.
[38] Aulehla A, Pourquie O. Oscillating signaling pathways during embryonic development[J]. Curr Opin Cell Biol, 2008, 20(6): 632-637.
[39] Fujimuro M, Hayward SD. The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus manipulates the activity of glycogen synthase kinase-3beta[J]. J Virol, 2003, 77(14): 8019-8030.
[40] Quyn AJ, Steele RJ, Carey FA, Nathke IS. Prognostic and therapeutic implications of Apc mutations in colorectal cancer[J]. Surgeon, 2008, 6(6): 350-356.
[41] Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS, Hayward SD. A novel viral mechanism for dysregulation of beta-catenin in Kaposi's sarcoma-associated herpesvirus latency[J]. Nat Med, 2003, 9(3): 300-306.
[42] Verma SC, Lan K, Robertson E. Structure and function of latency-associated nuclearantigen[J]. Curr Top Microbiol Immunol, 2007, 312: 101-136.
[43] Ohsaki E, Suzuki T, Karayama M, Ueda K. Accumulation of LANA at nuclear matrix fraction is important for Kaposi's sarcoma-associated herpesvirus replication in latency[J]. Virus Res, 2009, 139(1): 74-84.
[44] Cheng F, Weidner-Glunde M, Varjosalo M, Rainio EM, Lehtonen A, Schulz TF, Koskinen PJ, Taipale J, Ojala PM. KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA[J]. PLoS Pathog, 2009, 5(3): e1000324.
[45] Sarek G, Kurki S, Enback J, Iotzova G, Haas J, Laakkonen P, Laiho M, Ojala PM. Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas[J]. J Clin Invest, 2007, 117(4): 1019-1028.
[46] Griffiths R, Whitehouse A. Herpesvirus saimiri episomal persistence is maintained via interaction between open reading frame 73 and the cellular chromosome-associated protein MeCP2[J]. J Virol, 2007, 81(8): 4021-4032.
[47] Lan K, Verma SC, Murakami M, Bajaj B, Kaul R, Robertson ES. Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein[J]. Proc Natl Acad Sci U S A, 2007, 104(41): 16287-16292.
[48] Fujimuro M, Hayward SD. Manipulation of glycogen-synthase kinase-3 activity in KSHV-associated cancers[J]. J Mol Med, 2004, 82(4): 223-231.
[49] An FQ, Compitello N, Horwitz E, Sramkoski M, Knudsen ES, Renne R. The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest[J]. J Biol Chem, 2005, 280(5): 3862-3874.
[50] Fakhari FD, Jeong JH, Kanan Y, Dittmer DP. The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma[J]. J Clin Invest, 2006, 116(3): 735-742.
[51] Liu J, Martin H, Shamay M, Woodard C, Tang QQ, Hayward SD. Kaposi's sarcoma-associated herpesvirus LANA protein downregulates nuclear glycogen synthase kinase 3 activity and consequently blocks differentiation[J]. J Virol, 2007, 81(9): 4722-4731.
[52] Friborg J, Jr., Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death[J]. Nature, 1999, 402(6764): 889-894.
[53] Mansouri M, Rose PP, Moses AV, Fruh K. Remodeling of endothelial adherens junctions by Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 2008, 82(19): 9615-9628.
[54] An J, Lichtenstein AK, Brent G, Rettig MB. The Kaposi sarcoma-associated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element[J]. Blood, 2002, 99(2): 649-654.
[55] An J, Sun Y, Sun R, Rettig MB. Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and JNK/AP1 pathways[J]. Oncogene, 2003, 22(22): 3371-3385.
[56] An J, Sun Y, Rettig MB. Transcriptional coactivation of c-Jun by the KSHV-encoded LANA[J]. Blood, 2004, 103(1): 222-228.
[57] Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B. ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection[J]. J Virol, 2005, 79(16): 10308-10329.
[58] Xie J, Pan H, Yoo S, Gao SJ. Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways[J]. J Virol, 2005, 79(24): 15027-15037.
[59] Naranatt PP, Akula SM, Zien CA, Krishnan HH, Chandran B. Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity[J]. J Virol, 2003, 77(2): 1524-1539.
[60] Ford PW, Bryan BA, Dyson OF, Weidner DA, Chintalgattu V, Akula SM. Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency[J]. J Gen Virol, 2006, 87(Pt 5): 1139-1144.
[61] Cohen A, Brodie C, Sarid R. An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus[J]. J Gen Virol, 2006, 87(Pt 4): 795-802.
[62] Sadler R, Wu L, Forghani B, Renne R, Zhong W, Herndier B, Ganem D. A complex translational program generates multiple novel proteins from the latently expressed kaposin (K12) locus of Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 1999, 73(7): 5722-5730.
[63] McCormick C, Ganem D. The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs[J]. Science, 2005, 307(5710): 739-741.
[64] Li H, Komatsu T, Dezube BJ, Kaye KM. The Kaposi's sarcoma-associated herpesvirus K12 transcript from a primary effusion lymphoma contains complex repeat elements, is spliced, and initiates from a novel promoter[J]. J Virol, 2002, 76(23): 11880-11888.
[65] Kliche S, Nagel W, Kremmer E, Atzler C, Ege A, Knorr T, Koszinowski U, Kolanus W, Haas J. Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1[J]. Mol Cell, 2001, 7(4): 833-843.
[66] Lanier LL. Viral immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling in cell transformation and cancer[J]. Trends Cell Biol, 2006, 16(8): 388-390.
[67] Chen SY, Lu J, Shih YC, Tsai CH. Epstein-Barr virus latent membrane protein 2A regulates c-Jun protein through extracellular signal-regulated kinase[J]. J Virol, 2002, 76(18): 9556-9561.
[68] Wang L, Dittmer DP, Tomlinson CC, Fakhari FD, Damania B. Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus[J]. Cancer Res, 2006, 66(7): 3658-3666.
[69] Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator[J]. Nature, 1998, 391(6662): 86-89.
[70] Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF. Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein[J]. J Virol, 2003, 77(17): 9346-9358.
[71] Hamza MS, Reyes RA, Izumiya Y, Wisdom R, Kung HJ, Luciw PA. ORF36 protein kinase of Kaposi's sarcoma herpesvirus activates the c-Jun N-terminal kinase signaling pathway[J]. J Biol Chem, 2004, 279(37): 38325-38330.
[72] Lee BS, Lee SH, Feng P, Chang H, Cho NH, Jung JU. Characterization of the Kaposi's sarcoma-associated herpesvirus K1 signalosome[J]. J Virol, 2005, 79(19): 12173-12184.
[73] Gonzalez CM, Wong EL, Bowser BS, Hong GK, Kenney S, Damania B. Identification and characterization of the Orf49 protein of Kaposi's sarcoma-associated herpesvirus[J]. J Virol, 2006, 80(6): 3062-3070.
[74] Verma A, Kambhampati S, Parmar S, Platanias LC. Jak family of kinases in cancer[J]. Cancer Metastasis Rev, 2003, 22(4): 423-434.
[75] Bromberg J, Darnell JE, Jr. The role of STATs in transcriptional control and their impacton cellular function[J]. Oncogene, 2000, 19(21): 2468-2473.
[76] Darnell JE, Jr. STATs and gene regulation[J]. Science, 1997, 277(5332): 1630-1635.
[77] Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE, Jr. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions[J]. Cell, 1994, 76(5): 821-828.
[78] Burger M, Hartmann T, Burger JA, Schraufstatter I. KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway[J]. Oncogene, 2005, 24(12): 2067-2075.
[79] Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway[J]. Biochem J, 1998, 334 ( Pt 2): 297-314.
[80] Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit[J]. J Biol Chem, 1997, 272(31): 19625-19631.
[81] Wan X, Wang H, Nicholas J. Human herpesvirus 8 interleukin-6 (vIL-6) signals through gp130 but has structural and receptor-binding properties distinct from those of human IL-6[J]. J Virol, 1999, 73(10): 8268-8278.
[82] Meads MB, Medveczky PG. Kaposi's sarcoma-associated herpesvirus-encoded viral interleukin-6 is secreted and modified differently than human interleukin-6: evidence for a unique autocrine signaling mechanism[J]. J Biol Chem, 2004, 279(50): 51793-51803.
[83] Punjabi AS, Carroll PA, Chen L, Lagunoff M. Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells[J]. J Virol, 2007, 81(5): 2449-2458.
[84] Zeng Y, Zhang X, Huang Z, Cheng L, Yao S, Qin D, Chen X, Tang Q, Lv Z, Zhang L, Lu C. Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: role of JAK/STAT signaling[J]. J Virol, 2007, 81(5): 2401-2417.
[85] Brown HJ, Song MJ, Deng H, Wu TT, Cheng G, Sun R. NF-kappaB inhibits gammaherpesvirus lytic replication[J]. J Virol, 2003, 77(15): 8532-8540.
[86] Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex[J]. J Biol Chem, 2002, 277(16): 13745-13751.
[87] Field N, Low W, Daniels M, Howell S, Daviet L, Boshoff C, Collins M. KSHV vFLIP binds to IKK-gamma to activate IKK[J]. J Cell Sci, 2003, 116(Pt 18): 3721-3728.
[88] Chang MS, Lee HS, Jung EJ, Kim CW, Lee BL, Kim WH. Cell-cycle regulators, bcl-2 and NF-kappaB in Epstein-Barr virus-positive gastric carcinomas[J]. Int J Oncol, 2005, 27(5): 1265-1272.