The Stress-response protein prostate-associated gene 4, interacts with c-Jun and potentiates its transactivation

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• 作者：Krithika Rajagopalan ; Ruoyi Qiu ; Steven M. Mooney ; Shweta Rao ; Takumi Shiraishi ; Elizabeth Sacho ; Hongying Huang ; Ellen Shapiro ; Keith R. Weninger ; Prakash Kulkarni
• 关键词：BPH ; benign prostatic hyperplasia ; BSA ; bovine serum albumin ; CD ; circular dichroism ; DLS ; dynamic light scattering ; DMSO ; Dimethyl sulfoxide ; DBD ; DNA-binding domain ; IPTG ; Isopropyl 1-thio-尾-d-galactopyranoside ; NMR ; nuclear magnetic resonance ; PAGE4 ; Prostate Associated Gene 4 ; PBS ; Phosphate Buffered Saline ; PCa ; prostate cancer ; PC ; phosphatidylcholine ; PE ; phosphatidylethanolamine ; PIA ; proliferative inflammatory atrophy ; PIN ; prostatic intraepithelial neoplasia ; PINs ; protein interaction
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：February, 2014
• 年：2014
• 卷：1842
• 期：2
• 页码：154-163
• 全文大小：1260 K

文摘

The Cancer/Testis Antigen (CTA), Prostate-associated Gene 4 (PAGE4), is a stress-response protein that is upregulated in prostate cancer (PCa) especially in precursor lesions that result from inflammatory stress. In cells under stress, translocation of PAGE4 to mitochondria increases while production of reactive oxygen species decreases. Furthermore, PAGE4 is also upregulated in human fetal prostate, underscoring its potential role in development. However, the proteins that interact with PAGE4 and the mechanisms underlying its pleiotropic functions in prostatic development and disease remain unknown. Here, we identified c-Jun as a PAGE4 interacting partner. We show that both PAGE4 and c-Jun are overexpressed in the human fetal prostate; and in cell-based assays, PAGE4 robustly potentiates c-Jun transactivation. Single-molecule F枚rster resonance energy transfer experiments indicate that upon binding to c-Jun, PAGE4 undergoes conformational changes. However, no interaction is observed in presence of BSA or unilamellar vesicles containing the mitochondrial inner membrane diphosphatidylglycerol lipid marker cardiolipin. Together, our data indicate that PAGE4 specifically interacts with c-Jun and that, conformational dynamics may account for its observed pleiotropic functions. To our knowledge, this is the first report demonstrating crosstalk between a CTA and a proto-oncogene. Disrupting PAGE4/c-Jun interactions using small molecules may represent a novel therapeutic strategy for PCa.