摘要
星形细胞肿瘤(astrocytoma)是人类常见的恶性脑肿瘤之一,也是脑胶质瘤中最常见的病理类型。现已证明星形细胞肿瘤的形成与一定的内环境改变和基因变异有关,是一个多因素、多步骤的癌基因激活和抑癌基因失活参与的协同积累过程,但是星形细胞肿瘤的发病原因尚无定论,需要进一步研究。
Axin是1997年发现的,最初被认为是Wnt通路的抑制因子,后来的研究显示其能够负性调控胚胎的体轴发育。进一步的研究表明Axin还是抑癌基因,与多种肿瘤的发生发展密切相关。然而,目前Axin在星形细胞肿瘤发生与发展过程中的作用及机制尚不明确。本课题对Axin在不同级别的星形细胞肿瘤中的表达水平变化,以及其与星形细胞肿瘤的发生发展关系进行了研究,同时通过Axin过表达/沉默表达探讨其对星形细胞肿瘤的影响及其作用机制。
【目的】
1.研究Axin的表达与星形细胞肿瘤发生发展的相关性;2.从功能方面探讨Axin对星形细胞肿瘤细胞生长和凋亡的影响;3.研究Axin对星形细胞肿瘤细胞生长和凋亡的影响机制;4.探讨Axin下游分子β-catenin的表达分布,及其与星形细胞肿瘤患者预后的关系。
【方法】
1.利用反转录PCR(RT-PCR)和免疫组化的方法检测Axin在不同级别星形细胞肿瘤组织中的表达变化;2.构建Axin真核表达载体,并通过脂质体转染和G418筛选建立稳定高表达Axin的星形细胞肿瘤C6细胞系;3.设计合成Axin特异性siRNA,沉默Axin基因的表达;4.利用MTT实验、流式细胞仪、克隆形成实验、TUNEL染色、Hoechst染色等研究Axin对星形细胞肿瘤细胞C6生长和凋亡的影响;5.通过反转录PCR或Real-time PCR检测细胞中相关基因的mRNA水平变化;6.通过Western blot检测细胞中相关蛋白的表达水平;7.用免疫组织化学染色的方法检测β-catenin在星形细胞肿瘤中的表达和细胞定位,分析β-catenin的表达与患者预后的关系。
【结果】
1. Axin的表达水平与星形细胞肿瘤的级别相关
我们利用RT-PCR检测了不同级别星形细胞肿瘤中Axin mRNA的表达情况,发现2例WHO II级星形细胞肿瘤中均可检测到Axin mRNA,2例WHO III级间变型星形细胞肿瘤中有1例检测到Axin mRNA,而2例WHO IV级胶质母细胞瘤中没有发现Axin mRNA;对96例不同级别星形细胞肿瘤的免疫组织化学染色结果显示,Axin主要分布在肿瘤细胞的胞浆;33/96例星形细胞肿瘤Axin表达阳性(34.4%),其中23/49例(46.9%)为WHO II级星形细胞肿瘤,8/31例(25.8%)为WHO III级间变型星形细胞肿瘤,2/16(12.5%)例为WHO IV级胶质母细胞瘤;Spearman相关性统计分析表明Axin的表达水平与星形细胞肿瘤的分级呈负相关;但与患者的年龄、性别和肿瘤的发生部位无相关性。结果显示Axin随着星形细胞肿瘤级别的增高,其表达率降低,提示Axin在星形细胞肿瘤的进展过程中发挥重要作用。
2. Axin明显抑制星形细胞肿瘤C6细胞增殖并诱导其凋亡
流式细胞仪分析结果显示,Axin过表达使G2+S期细胞的分布比例降低而G1期被阻滞,而用siRNA Axin沉默Axin基因后与对照组细胞相比G2+S期细胞的分布比例上升;MTT实验结果显示,过表达Axin细胞组的细胞增殖水平明显低于对照组细胞的增殖水平,转染Axin组的细胞生长受到明显的抑制,且随着时间的推移,抑制程度明显增加;同样,过表达Axin使细胞的克隆形成能力明显低于对照组细胞;TUNEL和免疫荧光检测结果显示过表达Axin的细胞凋亡率明显高于对照组细胞的凋亡率。综合以上结果说明,Axin可诱导星形细胞肿瘤细胞凋亡并抑制其增殖,Axin在星形细胞肿瘤中发挥肿瘤抑制因子的功能。
3. Axin主要通过p53通路抑制星形细胞肿瘤细胞C6生长并诱导其凋亡
我们的预实验(RT-PCR)显示,过表达Axin后,mRNA表达量变化最明显的为p53基因,而β-catenin的总表达量无明显改变。我们进一步利用Real-time PCR方法检测p53及其下游基因的mRNA表达情况,同时通过Western blot的方法检测p53及下游相关蛋白的表达。结果发现,转染pIRES2-EGFP-Axin组p53的mRNA表达量比未转染对照组明显升高(与RT-PCR结果一致),p21的mRNA水平也相应升高,而Cyclin D1的mRNA水平下降;同样,Western blot也显示p53和p21的蛋白表达水平升高,而Cyclin D1的蛋白水平下降;此外,Axin过表达后,p53通路中与凋亡相关的重要分子Bax的表达量亦增高。
用p53的特异性抑制剂pifithrin-α处理细胞后,pifithrin-α处理组与未处理组相比,p53和p21的表达量出现降低,而Cyclin D1的表达量升高,Bax的表达量降低;而且,用pifithrin-α处理组细胞的凋亡指数为19.5%,亦明显低于未处理组(36.5%);而对照组的细胞的凋亡指数用pifithrin-α处理前后没有明显变化;用pifithrin-α处理组G2+S期细胞分布(36.2%)高于未处理组(25.4%),而G1期细胞分布(63.8%)低于未处理组(74.6%),然而对照组(未转染Axin组)用pifithrin-α处理前后在G2+S期和G1期的细胞分布没有明显变化。
以上结果提示,p53抑制剂pifithrin-α可逆转由Axin诱导的p53及其下游基因的表达,从而抵抗Axin过表达所致的星形细胞肿瘤细胞C6生长的抑制,同时,由Axin诱导的星形细胞肿瘤细胞C6的凋亡作用也受到抑制,说明在星形细胞肿瘤中,p53通路参与了Axin所产生的生长抑制和诱导凋亡作用。
为了确定星形细胞肿瘤中β-catenin在Axin的诱导凋亡和生长抑制中的作用,我们采用RT-PCR的方法检测β-catenin mRNA的表达水平,发现其总量没有发生改变。然而,Western blot结果显示未转染Axin前,胞浆内的β-catenin含量比胞核内多,而转染Axin后,胞浆内的β-catenin比细胞核内的减少。进一步用免疫细胞化学染色检测转染Axin前后β-catenin含量的变化,转染Axin后,β-catenin胞核表达阳性的细胞数比转染空载体的细胞数量增多。
4.β-catenin表达量高的星形细胞肿瘤患者的预后差
尽管没有证据显示Axin在星形细胞肿瘤中能够直接影响β-catenin的表达水平,但是作为Wnt通路中的重要分子,β-catenin对星形细胞肿瘤可能有一定的影响。我们对65例星形细胞肿瘤组织标本进行了β-catenin的表达分布检测,发现β-catenin在肿瘤细胞胞浆、胞膜和胞核中均有表达,Spearman相关性分析结果显示星形细胞肿瘤的级别与β-catenin的分布(细胞浆、细胞膜、细胞核)没有相关性,表明β-catenin的核易位与星形细胞肿瘤的整体恶性程度无关;通过对不同级别星形细胞肿瘤进行分析还发现,β-catenin的表达(包括细胞浆、膜和核)与星形细胞肿瘤的级别无相关性;而且,β-catenin的表达与肿瘤大小、年龄、性别和发生部位等均没有相关性;但是通过对β-catenin的表达与患者两年生存率的相关性进行研究发现,β-catenin的表达与患者两年生存率有相关性,患者两年生存率随着β-catenin表达量的增高而下降;生存曲线显示,β-catenin高表达的患者预后比低表达的患者预后差。
【结论】
本研究发现Axin是一个与星形细胞肿瘤发生发展密切相关的基因,其表达随着星形细胞肿瘤级别的增高而降低;同时我们发现在星形细胞肿瘤中Axin通过p53通路抑制星形细胞肿瘤细胞C6的增殖并诱导其凋亡;而作为Axin下游基因,β-catenin在星形细胞肿瘤细胞浆、核、膜不同部位的分布与星形细胞肿瘤的恶性程度无明显相关性,但是β-catenin的表达与患者的预后密切相关。
Astrocytoma is one of the most common malignant brain tumors, and is also the most common glioma type of pathology. Modern molecular genetic analyses have revealed that the progression of astrocytic tumors results from accumulating inactivation of different tumors suppressor genes and/or amplification of certain oncogene, while the molecular mechanisms of the carcinogenesis and progression of astrocytoma have not been clarified.
Axin was found in 1997, initially be considered as an inhibitor of the Wnt signaling pathway, and later studies have showed that Axin be able to negatively control axis development. Further research showed that Axin is a very important tumor suppressor, with a wide variety of tumor is closely related to the occurrence and development. Until now, the role of Axin in astrocytoma and its underlying mechanism are still unknown. In this study, we detected the expression of Axin in astrocytoma and explored the relationship between Axin expression and the clinicopathologic factors of astrocytoma. Furthermore, the role and possible mechanism of Axin in astrocytoma were investigated by Axin overexpression and Axin silencing.
【Objectives】
1. To investigate the relationship between Axin expression and progression of astrocytoam by RT-PCR and immunohistochemistry staining; 2. To study the effects of Axin on astrocytoma cell growth and apoptosis; 3. To explore the possible mechanism of Axin on cell growth and apoptosis in astrocytoma; 4. To study the localization ofβ-catenin in astrocytoma,and evaluate the patient survival with the level ofβ-catenin expression.
【Methods】
1. The expression of Axin in human astrocytoma tissues was detected by RT-PCR and immunohistochemical staining; 2. The eukaryotic expression vector with Axin was constructed and the C6 cell line stably expressing Axin gene was established; 3. The Axin gene was silenced in C6 cells by treating with Axin siRNA; 4. The effects of Axin on growth and apoptosis of astrocytoma C6 cells were respectively investigated by MTT assay, flow cytometry, colony formation assay, TUNEL staining and Hoechst staining; 5. The mRNA expression was determined by RT-PCR or Real-time PCR; 6. The protein expression level was determined by Western blot; 7. The expression and localization ofβ-catenin in astrocytoma was detected by immunohistochemistry staining.
【Results】
1. Axin expression correlated with the grades of astrocytoma
To investigate the relationship between the expression of Axin and progression of astrocytoma, the RT-PCR and immunohistochemistry were employed to investigate the expression of Axin in astrocytoma. The Axin mRNA was detected in 2 of 2 samples of grade II astrocytoma. However, only 1 of 2 samples of grade III and 0 of 2 samples of grade IV astrocytoma showed Axin mRNA expression. The immunohistochemistry results showed that the localization of Axin was mainly preserved in cytoplasma. Thirty-three cases in the 96 samples of astrocytoma showed Axin positive expression (34.4%). Twenty-three cases of 49 grade II samples (46.9%), 8 of 31 grade III samples (25.8%), 2 of 16 grade IV samples (12.5%) showed Axin positive staining. The spearman’s correlation test revealed that Axin positive expression was inversely correlated with the grades of astrocytoma significantly. The expression level of Axin didn’t differ significantly by age, sex, and location.
2. Axin could induce apoptosis, and inhibite proliferative activity in astrocytoma cells
The flow cytometry results indicated that overexpression of Axin could reduce the distribution of G2+ S-phase cells and led to G1-phase cell cycle arrested. Furthermore, silencing of Axin in C6 cells could increase the distribution of G2+ S-phase cells. MTT assay showed that the level of proliferation in C6 cells with overexpressed Axin was significantly lower than that of C6 cells or C6 cells transfected with pIRES2-EGFP. Similarly, the colony-forming ability markedly reduced in the cells overexpressed with Axin compared with the C6 cell transfected with EGFP. TUNEL staining showed that apoptotic index of cells with overexpressed Axin significantly increased compared to the pCMV5 group and the blank control.
3. Axin induce C6 cell apoptosis and reduce cell proliferation mainly by activating p53 pathway
The preliminary experiment showed that overexpression of Axin could increase p53 mRNA level significantly, and the total level mRNA level ofβ-catenin was not changed. And then Real-time PCR and Western blot were used to detect p53 and its downstream genes mRNA and protein expression. The results showed that the mRNA level of p53 in C6 cells overexpressed with Axin markedly increased compared with the C6 cells transfected with pIRES2-EGFP. Meanwhile, the mRNA level of p21 significantly increased, and the Cyclin D1 mRNA decreased compared with the control groups. Similarly, the immunoblotting analysis revealed that Axin could induce the expression of p53 and p21 in C6 cells, and reduce the expression of Cyclin D1. In addition, the apoptosis relative molecule Bax was increased after transfected with Axin gene.
After treated the cells with pifithrin-α, the results showed that the C6 cells with endogenous or overexpressed Axin treated with p53 inhibitor resulted in significantly reduction of p53, p21 and Bax, and induction of Cyclin D1 compared with C6 cells overexpressed with Axin, suggesting the p53 inhibitor could counteract the effect of Axin.
Furthermore, the apoptotic index of C6-Axin treated with p53 inhibitor was 19.5%. Howere, There are not obviously changes between the groups which treated with and non-treated with pifithrin-αin C6-EGFP cells.The distribution of G2+ S-phase cells treated with pifithrin-αincreased, and G1-phase cells reduced compared to untreated cells.
All results suggested the p53 inhibitor could antagonize the cell growth and death-inducing effect of Axin. Collectively, these results demonstrate that p53 pathway plays an importrant role in reduced cell ploliferation and induced apoptosis by Axin in astrocytoma. 14
Real-time PCR was used to identify theβ-catenin mRNA level in astrocytoma, and showed that the total mRNA was not changed. And then, we detected theβ-catenin levels in cytoplasma and nucleus respectively by Western blot. This result indicates thatβ-catenin level in C6 cell cytoplasma higher than that in nuclear, but lower than that in nuclear after transfected with Axin gene. The immunocytochemical staining result showed that theβ-catenin nucleus positive cells in C6-Axin were higher than that in C6-Vector cells.
4. Increased expression ofβ-catenin with poor prognosis
As one of the most important molecule in Wnt signal pathway,β-catenin might play role on the progression of astrocytoma. 65 astrocytoma samples were detected by immunohistochemistry staining. The result showed that the expression ofβ-catenin was preserved in cytoplasma, membrane and nucleus. Spearman analysis showed that the distribution ofβ-catenin (cytoplasma, membrane and nucleus) was not correlated with the grades of astrocytoma, indicated thatβ-catenin translocation was not influence the malignance of astrocytoma. We also found that there were significant correlation betweenβ-catenin expression and 2-year survival. The expression ofβ-catenin was not correlated with the grades, tumor size, age, sex, and tumor location. Moreover, the survival curves for patients with astrocytoma showing low expression ofβ-catenin tend to be associated with good prognosis, but high expression ofβ-catenin tend to be associated with poor prognosis.
【Conclusion】
We provide evidence that Axin is associated with the progression of astrocytoma, with the increase of astrocytoma grades the expression of Axin decreased. Meanwhile, we found that, in astrocytoma, Axin induces cell death and reduces cell proliferation by activiting p53 pathway. As a downstream gene of Axin,β-catenin expression in cytoplasma, membrane and nucleus was not correlated with the grades of astrocytoma, but the expression ofβ-catenin was correlated with the prognosis of patients.
引文
1. Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, 3rd, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 1997, 90(1):181-192.
2. Kikuchi A. Roles of Axin in the Wnt signalling pathway. Cell Signal 1999, 11(11):777-788.
3. Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 1998, 280(5363):596-599.
4. Yamamoto H, Kishida S, Uochi T, Ikeda S, Koyama S, Asashima M, Kikuchi A. Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. Mol Cell Biol 1998, 18(5):2867-2875.
5. Kikuchi A. Modulation of Wnt signaling by Axin and Axil. Cytokine Growth Factor Rev 1999, 10(3-4):255-265.
6. Kishida S, Yamamoto H, Ikeda S, Kishida M, Sakamoto I, Koyama S, Kikuchi A. Axin, a negative regulator of the wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of beta-catenin. J Biol Chem 1998, 273(18):10823-10826.
7. Hedgepeth CM, Deardorff MA, Klein PS. Xenopus axin interacts with glycogen synthase kinase-3 beta and is expressed in the anterior midbrain. Mech Dev 1999, 80(2):147-151.
8. Hsu W, Zeng L, Costantini F. Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain. J Biol Chem 1999, 274(6):3439-3445.
9. Zhang Y, Neo SY, Wang X, Han J, Lin SC. Axin forms a complex with MEKK1 and activates c-Jun NH(2)-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling. J Biol Chem 1999, 274(49):35247-35254.
10. Zhang Y, Qiu WJ, Liu DX, Neo SY, He X, Lin SC. Differential molecular assemblies underlie the dual function of Axin in modulating the WNT and JNK pathways. J Biol Chem 2001, 276(34):32152-32159.
11. Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC. Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways. J Biol Chem 2002, 277(20):17706-17712.
12. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, anegative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. Embo J 1998, 17(5):1371-1384.
13. Schwarz-Romond T, Asbrand C, Bakkers J, Kuhl M, Schaeffer HJ, Huelsken J, Behrens J, Hammerschmidt M, Birchmeier W. The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev 2002, 16(16):2073-2084.
14. Mao J, Wang J, Liu B, Pan W, Farr GH, 3rd, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 2001, 7(4):801-809.
15. Kusano S, Raab-Traub N. I-mfa domain proteins interact with Axin and affect its regulation of the Wnt and c-Jun N-terminal kinase signaling pathways. Mol Cell Biol 2002, 22(18):6393-6405.
16. Kadoya T, Kishida S, Fukui A, Hinoi T, Michiue T, Asashima M, Kikuchi A. Inhibition of Wnt signaling pathway by a novel axin-binding protein. J Biol Chem 2000, 275(47):37030-37037.
17. Nishida T, Kaneko F, Kitagawa M, Yasuda H. Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting beta-catenin degradation. J Biol Chem 2001, 276(42):39060-39066.
18. Kadoya T, Yamamoto H, Suzuki T, Yukita A, Fukui A, Michiue T, Asahara T, Tanaka K, Asashima M, Kikuchi A. Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of beta-catenin. Mol Cell Biol 2002, 22(11):3803-3819.
19. Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, Kikuchi A, Miyazono K, Kato M. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol 2001, 21(15):5132-5141.
20. Kishida S, Yamamoto H, Hino S, Ikeda S, Kishida M, Kikuchi A. DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability. Mol Cell Biol 1999, 19(6):4414-4422.
21. Julius MA, Schelbert B, Hsu W, Fitzpatrick E, Jho E, Fagotto F, Costantini F, Kitajewski J. Domains of axin and disheveled required for interaction and function in wnt signaling. Biochem Biophys Res Commun 2000, 276(3):1162-1169.
22. Luo W, Ng WW, Jin LH, Ye Z, Han J, Lin SC. Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. J Biol Chem2003, 278(39):37451-37458.
23. Rui HL, Fan E, Zhou HM, Xu Z, Zhang Y, Lin SC. SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling. J Biol Chem 2002, 277(45):42981-42986.
24. Sussman DJ, Klingensmith J, Salinas P,et al. Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled. Dev Biol 1994, 166(73-86).
25. Salahshor S, Woodgett JR. The links between axin and carcinogenesis. J Clin Pathol 2005, 58(3):225-236.
26. Luo W, Lin SC. Axin: a master scaffold for multiple signaling pathways. Neurosignals 2004, 13(3):99-113.
27. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000, 24(3):245-250.
28. Penton A, Wodarz A, Nusse R. A mutational analysis of dishevelled in Drosophila defines novel domains in the dishevelled protein as well as novel suppressing alleles of axin. Genetics 2002, 161(2):747-762.
29. Gumbiner BM, McCrea PD. Catenins as mediators of the cytoplasmic functions of cadherins. J Cell Sci Suppl 1993, 17:155-158.
30. Schneider S, Herrenknecht K, Butz S, Kemler R, Hausen P. Catenins in Xenopus embryogenesis and their relation to the cadherin-mediated cell-cell adhesion system. Development 1993, 118(2):629-640.
31. Piddini E, Vincent JP. Interpretation of the wingless gradient requires signaling-induced self-inhibition. Cell 2009, 136(2):296-307.
32. Li L, Yuan H, Weaver CD, Mao J, Farr GH, 3rd, Sussman DJ, Jonkers J, Kimelman D, Wu D. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. Embo J 1999, 18(15):4233-4240.
33. Farr GH, 3rd, Ferkey DM, Yost C, Pierce SB, Weaver C, Kimelman D. Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification. J Cell Biol 2000, 148(4):691-702.
34. behrens J, von Kries JP, Kuhl M, et al. . Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996, 382:638-642.
35. He TC SA, Rago C, et al. . Identification of c-MYC as a target of the APC pathway. Science 1998, 281:1509-1512.
36. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. The cyclin D1 gene is a target of the beta-catenin/LEF-1pathway. Proc Natl Acad Sci U S A 1999, 96(10):5522-5527.
37. Sakanaka C, Weiss JB, Williams LT. Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proc Natl Acad Sci U S A 1998, 95(6):3020-3023.
38. Hamada F, Tomoyasu Y, Takatsu Y, Nakamura M, Nagai S, Suzuki A, Fujita F, Shibuya H, Toyoshima K, Ueno N, Akiyama T. Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin. Science 1999, 283(5408):1739-1742.
39. Willert K, Shibamoto S, Nusse R. Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev 1999, 13(14):1768-1773.
40. Willert K, Logan CY, Arora A, Fish M, Nusse R. A Drosophila Axin homolog, Daxin, inhibits Wnt signaling. Development 1999, 126(18):4165-4173.
41. Korswagen HC, Coudreuse DY, Betist MC, van de Water S, Zivkovic D, Clevers HC. The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans. Genes Dev 2002, 16(10):1291-1302.
42. 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. Nat Med 2003, 9(3):300-306.
43. Hsu W, Shakya R, Costantini F. Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice. J Cell Biol 2001, 155(6):1055-1064.
44. Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. Embo J 2003, 22(3):494-501.
45. Sakanaka C, Williams LT. Functional domains of axin. Importance of the C terminus as an oligomerization domain. J Biol Chem 1999, 274(20):14090-14093.
46. Rubinfeld B AI, Porfiri E, et al. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly science 1996, 272:1023-1026.
47. Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 2002, 16(9):1066-1076.
48. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002, 108(6):837-847.
49. Peters JM MR, McKay JP,et al. Casein kinase 1 transduces Wnt signals. Nature 1999, 401:345-350.
50. AJ. H. Regulation of GSK-3beta: a cellular multiprocessor. cell 2001, 105(821-824).
51. Wu G, Huang H, Garcia Abreu J, He X. Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS ONE 2009, 4(3):e4926.
52. Morin PJ. beta-catenin signaling and cancer. Bioessays 1999, 21(12):1021-1030.
53. Henderson BR, Fagotto F. The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep 2002, 3(9):834-839.
54. Polakis P. Wnt signaling and cancer. Genes Dev 2000, 14(15):1837-1851.
55. Siriwardena BS, Kudo Y, Ogawa I, Tilakaratne WM, Takata T. Aberrant beta-catenin expression and adenomatous polyposis coli gene mutation in ameloblastoma and odontogenic carcinoma. Oral Oncol 2009, 45(2):103-108.
56. Olschwang S WB, Laurent-Puig P, et al. Genetic characterization of the APC locus involved in familial adenomatous polyposis Gastroenterology 1991, 101:154-160.
57. M. B. APC. Curr Biol 2003, 13:R215-216.
58. Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 1998, 8(10):573-581.
59. Hinoi T, Yamamoto H, Kishida M, Takada S, Kishida S, Kikuchi A. Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3 beta-dependent phosphorylation of beta-catenin and down-regulates beta-catenin. J Biol Chem 2000, 275(44):34399-34406.
60. Rubinfeld B AI, Porfiri E, et al. Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Cancer Res 1997, 57:4624-4630.
61. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells 1998, 3(6):395-403.
62. Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin. Proc Natl Acad Sci U S A 2004, 101(9):2882-2887.
63. Wiechens N, Heinle K, Englmeier L, Schohl A, Fagotto F. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin Pathway. J Biol Chem 2004, 279(7):5263-5267.
64. Wiechens N, Fagotto F. CRM1- and Ran-independent nuclear export ofbeta-catenin. Curr Biol 2001, 11(1):18-27.
65. Fukui A, Kishida S, Kikuchi A, Asashima M. Effects of rat Axin domains on axis formation in Xenopus embryos. Dev Growth Differ 2000, 42(5):489-498.
66. Itoh K, Krupnik VE, Sokol SY. Axis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and beta-catenin. Curr Biol 1998, 8(10):591-594.
67. Kofron M, Klein P, Zhang F, Houston DW, Schaible K, Wylie C, Heasman J. The role of maternal axin in patterning the Xenopus embryo. Dev Biol 2001, 237(1):183-201.
68. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. Science 2000, 287(5458):1606-1609.
69. Fagotto F, Jho E, Zeng L, Kurth T, Joos T, Kaufmann C, Costantini F. Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization. J Cell Biol 1999, 145(4):741-756.
70. Tolwinski NS, Wieschaus E. Rethinking WNT signaling. Trends Genet 2004, 20(4):177-181.
71. Gho M SF. Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila. nature 1998, 393:178-181.
72. Tada M, Smith JC. Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway. Development 2000, 127(10):2227-2238.
73. Wallingford JB, Rowning BA, Vogeli KM, Rothbacher U, Fraser SE, Harland RM. Dishevelled controls cell polarity during Xenopus gastrulation. Nature 2000, 405(6782):81-85.
74. Capelluto DG, Kutateladze TG, Habas R, Finkielstein CV, He X, Overduin M. The DIX domain targets dishevelled to actin stress fibres and vesicular membranes. Nature 2002, 419(6908):726-729.
75. Goold RG, Owen R, Gordon-Weeks PR. Glycogen synthase kinase 3beta phosphorylation of microtubule-associated protein 1B regulates the stability of microtubules in growth cones. J Cell Sci 1999, 112 ( Pt 19):3373-3384.
76. Lyu J, Costantini F, Jho EH, Joo CK. Ectopic expression of Axin blocks neuronal differentiation of embryonic carcinoma P19 cells. J Biol Chem 2003, 278(15):13487-13495.
77. Orme MH, Giannini AL, Vivanco MD, Kypta RM. Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells. Mol Cell Neurosci 2003, 24(3):673-686.
78. Herdegen T, Skene P, Bahr M. The c-Jun transcription factor--bipotentialmediator of neuronal death, survival and regeneration. Trends Neurosci 1997, 20(5):227-231.
79. Keyse SM. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr Opin Cell Biol 2000, 12(2):186-192.
80. Stoothoff WH, Bailey CD, Mi K, Lin SC, Johnson GV. Axin negatively affects tau phosphorylation by glycogen synthase kinase 3beta. J Neurochem 2002, 83(4):904-913.
81. Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell 1998, 1(4):543-551.
82. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998, 67:753-791.
83. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997, 390(6659):465-471.
84. Chakrabarty S, Fan D, Varani J. Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor beta 1 and beta 2. Int J Cancer 1990, 46(3):493-499.
85. Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, Searle J, Radford-Smith G, Young J, Leggett B. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 1998, 42(5):673-679.
86. Nishita M, Hashimoto MK, Ogata S, Laurent MN, Ueno N, Shibuya H, Cho KW. Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizer. Nature 2000, 403(6771):781-785.
87. Rui Y, Xu Z, Lin S, Li Q, Rui H, Luo W, Zhou HM, Cheung PY, Wu Z, Ye Z, Li P, Han J, Lin SC. Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. Embo J 2004, 23(23):4583-4594.
88. Lin SC, Li Q. Axin bridges Daxx to p53. Cell Res 2007, 17(4):301-302.
89. Li Q, Wang X, Wu X, Rui Y, Liu W, Wang J, Wang X, Liou YC, Ye Z, Lin SC. Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer Res 2007, 67(1):66-74.
90. Anderson CB, Neufeld KL, White RL. Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc Natl Acad Sci U S A 2002, 99(13):8683-8688.
91. Yardy GW, Bicknell DC, Wilding JL, Bartlett S, Liu Y, Winney B, Turner GD, Brewster SF, Bodmer WF. Mutations in the AXIN1 Gene in Advanced Prostate Cancer. Eur Urol 2008.
92. Pan KF, Liu WG, Zhang L, You WC, Lu YY. Mutations in components of the Wntsignaling pathway in gastric cancer. World J Gastroenterol 2008, 14(10):1570-1574.
93. Xu HT, Wang L, Lin D, Liu Y, Liu N, Yuan XM, Wang EH. Abnormal beta-catenin and reduced axin expression are associated with poor differentiation and progression in non-small cell lung cancer. Am J Clin Pathol 2006, 125(4):534-541.
94. Webster MT, Rozycka M, Sara E, Davis E, Smalley M, Young N, Dale TC, Wooster R. Sequence variants of the axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding. Genes Chromosomes Cancer 2000, 28(4):443-453.
95. Stevens MC, Cameron AH, Muir KR, Parkes SE, Reid H, Whitwell H. Descriptive epidemiology of primary central nervous system tumours in children: a population-based study. Clin Oncol (R Coll Radiol) 1991, 3(6):323-329.
96. Uthoff SM, Eichenberger MR, McAuliffe TL, Hamilton CJ, Galandiuk S. Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer. Mol Carcinog 2001, 31(1):56-62.
97. Zurawel RH, Chiappa SA, Allen C, Raffel C. Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 1998, 58(5):896-899.
98. Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 2002, 110(6):751-762.
99. Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. APC mutations in sporadic medulloblastomas. Am J Pathol 2000, 156(2):433-437.
100. Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sorensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 2001, 61(19):7039-7043.
101. Baeza N, Masuoka J, Kleihues P, Ohgaki H. AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene 2003, 22(4):632-636.
102. Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba H, Maekawa M. Role of Wnt pathway in medulloblastoma oncogenesis. Int J Cancer 2002, 101(2):198-201.
103. Lustig B, Behrens J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 2003, 129(4):199-221.
104. Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectaland liver tumors. Mol Cell Biol 2002, 22(4):1184-1193.
105. Yan D, Wiesmann M, Rohan M, Chan V, Jefferson AB, Guo L, Sakamoto D, Caothien RH, Fuller JH, Reinhard C, Garcia PD, Randazzo FM, Escobedo J, Fantl WJ, Williams LT. Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta -catenin signaling is activated in human colon tumors. Proc Natl Acad Sci U S A 2001, 98(26):14973-14978.
106. Harada N, Miyoshi H, Murai N, Oshima H, Tamai Y, Oshima M, Taketo MM. Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer Res 2002, 62(7):1971-1977.
107. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 1998, 95(15):8847-8851.
108. Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R, Hirohashi S. Beta-catenin accumulation and mutation of exon 3 of the beta-catenin gene in hepatocellular carcinoma. Jpn J Cancer Res 1999, 90(12):1301-1309.
109. Ihara A, Koizumi H, Hashizume R, Uchikoshi T. Expression of epithelial cadherin and alpha- and beta-catenins in nontumoral livers and hepatocellular carcinomas. Hepatology 1996, 23(6):1441-1447.
110. Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, Ohgaki H. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol 1999, 155(6):1795-1801.
111. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 2001, 120(7):1763-1773.
112. Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, Lee JY, Park CK. Mutations of beta-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis. Liver Int 2005, 25(1):70-76.
113. Kim YD, Park CH, Kim HS, Choi SK, Rew JS, Kim DY, Koh YS, Jeung KW, Lee KH, Lee JS, Juhng SW, Lee JH. Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma. J Gastroenterol Hepatol 2008, 23(1):110-118.
114. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001, 51(1):15-36.
115. Moreno-Bueno G, Hardisson D, Sanchez C, Sarrio D, Cassia R, Garcia-Rostan G, Prat J, Guo M, Herman JG, Matias-Guiu X, Esteller M, Palacios J.Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 2002, 21(52):7981-7990.
116. Saegusa M, Okayasu I. Frequent nuclear beta-catenin accumulation and associated mutations in endometrioid-type endometrial and ovarian carcinomas with squamous differentiation. J Pathol 2001, 194(1):59-67.
117. Taylor MD, Zhang X, Liu L, Hui CC, Mainprize TG, Scherer SW, Wainwright B, Hogg D, Rutka JT. Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling. Oncogene 2004, 23(26):4577-4583.
118. Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res 2001, 61(22):8247-8255.
119. Wagata T, Ishizaki K, Imamura M, Shimada Y, Ikenaga M, Tobe T. Deletion of 17p and amplification of the int-2 gene in esophageal carcinomas. Cancer Res 1991, 51(8):2113-2117.
120. Nakajima M, Fukuchi M, Miyazaki T, Masuda N, Kato H, Kuwano H. Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma. Br J Cancer 2003, 88(11):1734-1739.
121. de Castro J, Gamallo C, Palacios J, Moreno-Bueno G, Rodriguez N, Feliu J, Gonzalez-Baron M. beta-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcome. Virchows Arch 2000, 437(6):599-604.
122. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995, 9(4):401-406.
123. Truica CI, Byers S, Gelmann EP. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res 2000, 60(17):4709-4713.
124.邵秋杰,李青,金利华,等.胶质瘤中Axin基因点突变检测及表达研究.中华神经外科疾病研究杂志2003, 2(4):334-337.
125. Daa T, Kashima K, Kaku N, Suzuki M, Yokoyama S. Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma. Mod Pathol 2004, 17(12):1475-1482.
126. Miao J, Kusafuka T, Udatsu Y, Okada A. Axin, the main component of the Wnt signaling pathway, is not mutated in kidney tumors in children. Int J Mol Med 2002, 9(4):377-379.
127. Elias JM, Margiotta M, Gaborc D. Sensitivity and detection efficiency of the peroxidase antiperoxidase (PAP), avidin-biotin peroxidase complex (ABC), and peroxidase-labeled avidin-biotin (LAB) methods. Am J ClinPathol 1989, 92(1):62-67.
128. Zhou CX, Gao Y. Frequent genetic alterations and reduced expression of the Axin1 gene in oral squamous cell carcinoma: involvement in tumor progression and metastasis. Oncol Rep 2007, 17(1):73-79.
129. Xu HT, Wei Q, Liu Y, Yang LH, Dai SD, Han Y, Yu JH, Liu N, Wang EH. Overexpression of axin downregulates TCF-4 and inhibits the development of lung cancer. Ann Surg Oncol 2007, 14(11):3251-3259.
130. Tortosa A, Vinolas N, Villa S, Verger E, Gil JM, Brell M, Caral L, Pujol T, Acebes JJ, Ribalta T, Ferrer I, Graus F. Prognostic implication of clinical, radiologic, and pathologic features in patients with anaplastic gliomas. Cancer 2003, 97(4):1063-1071.
131. Castellani P, Borsi L, Carnemolla B, Biro A, Dorcaratto A, Viale GL, Neri D, Zardi L. Differentiation between high- and low-grade astrocytoma using a human recombinant antibody to the extra domain-B of fibronectin. Am J Pathol 2002, 161(5):1695-1700.
132. Zolota V, Tsamandas AC, Aroukatos P, Panagiotopoulos V, Maraziotis T, Poulos C, Scopa CD. Expression of cell cycle inhibitors p21, p27, p14 and p16 in gliomas. Correlation with classic prognostic factors and patients' outcome. Neuropathology 2008, 28(1):35-42.
133. Mao Y, Zhou L, Zhu W, Wang X, Yang G, Xie L, Mao X, Jin K. Proliferative status of tumor stem cells may be correlated with malignancy grade of human astrocytomas. Front Biosci 2007, 12:2252-2259.
134. Zhang LY, Li Q, Chen GS, Lin SC, Ye J, Si SY, Zhang F. [Construction of the eukaryotic expression vector pIRES2-EGFP-Axin and its expression in glioma cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2005, 21(4):408-410.
135. Lu J, Zhang F, Zhao D, Hong L, Min J, Zhang L, Li F, Yan Y, Li H, Ma Y, Li Q. ATRA-inhibited proliferation in glioma cells is associated with subcellular redistribution of beta-catenin via up-regulation of Axin. J Neurooncol 2008, 87(3):271-277.
136. Ishiguro H, Tsunoda T, Tanaka T, Fujii Y, Nakamura Y, Furukawa Y. Identification of AXUD1, a novel human gene induced by AXIN1 and its reduced expression in human carcinomas of the lung, liver, colon and kidney. Oncogene 2001, 20(36):5062-5066.
137. Donehower LA, Bradley A. The tumor suppressor p53. Biochim Biophys Acta 1993, 1155(2):181-205.
138. Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Jr., Giaccia AJ. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 1994, 14(9):6264-6277.
139. Ko LJ, Prives C. p53: puzzle and paradigm. Genes Dev 1996, 10(9):1054-1072.
140. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991, 51(23 Pt 1):6304-6311.
141. el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994, 54(5):1169-1174.
142. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004, 303(5660):1010-1014.
143. Li Z, Stanelle J, Leurs C, Hanenberg H, Putzer BM. Selection of novel mediators of E2F1-induced apoptosis through retroviral expression of an antisense cDNA library. Nucleic Acids Res 2005, 33(9):2813-2821.
144. Waldman T, Kinzler KW, Vogelstein B. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res 1995, 55(22):5187-5190.
145. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E, et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 1995, 6(4):387-400.
146. Crook T, Marston NJ, Sara EA, Vousden KH. Transcriptional activation by p53 correlates with suppression of growth but not transformation. Cell 1994, 79(5):817-827.
147. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW, Vogelstein B. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998, 282(5393):1497-1501.
148. Montes de Oca Luna R, Wagner DS, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 1995, 378(6553):203-206.
149. Leveillard T, Gorry P, Niederreither K, Wasylyk B. MDM2 expression during mouse embryogenesis and the requirement of p53. Mech Dev 1998, 74(1-2):189-193.
150. Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T, Van Dyke T. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 1994, 78(4):703-711.
151. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by trans-activation-deficient p53. Genes Dev 1995, 9(17):2170-2183.
152. Sabbatini P, Lin J, Levine AJ, White E. Essential role for p53-mediated transcription in E1A-induced apoptosis. Genes Dev 1995, 9(17):2184-2192.
153. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997,88(3):323-331.
154. Nakamura Y. Cleaning up on beta-catenin. Nat Med 1997, 3(5):499-500.
155. Gumbiner BM. Signal transduction of beta-catenin. Curr Opin Cell Biol 1995, 7(5):634-640.
156. Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci 1999, 56(5-6):523-537.
157. Akiyama T. Wnt/beta-catenin signaling. Cytokine Growth Factor Rev 2000, 11(4):273-282.
158. Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg 2000, 87(8):992-1005.
159. Woo DK, Kim HS, Lee HS, Kang YH, Yang HK, Kim WH. Altered expression and mutation of beta-catenin gene in gastric carcinomas and cell lines. Int J Cancer 2001, 95(2):108-113.
160. Grabsch H, Takeno S, Noguchi T, Hommel G, Gabbert HE, Mueller W. Different patterns of beta-catenin expression in gastric carcinomas: relationship with clinicopathological parameters and prognostic outcome. Histopathology 2001, 39(2):141-149.
161. Utsuki S, Sato Y, Oka H, Tsuchiya B, Suzuki S, Fujii K. Relationship between the expression of E-, N-cadherins and beta-catenin and tumor grade in astrocytomas. J Neurooncol 2002, 57(3):187-192.
162.吴秋良曾张饶张侯.细胞骨架蛋白α-和β-catenin在胶质瘤中的表达.中国肿瘤2004, 11(1):0738-0702.
163. Chou HY, Howng SL, Cheng TS, Hsiao YL, Lieu AS, Loh JK, Hwang SL, Lin CC, Hsu CM, Wang C, Lee CI, Lu PJ, Chou CK, Huang CY, Hong YR. GSKIP is homologous to the Axin GSK3beta interaction domain and functions as a negative regulator of GSK3beta. Biochemistry 2006, 45(38):11379-11389.