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- W2945183048 abstract "986 Introduction and Objectives: Modulation of androgen receptor may play an important role in normal growth and differentiation of prostate epithelial cells. AR alterations (amplification, elevated expression, mutation, co-activator/co-repressor dysfunction) leading to gain of AR functions are increasingly highlighted in prostate cancer. Materials and Methods: Our laboratory has recently contributed to comprehensive evaluation of the androgen regulated gene repertoire using SAGE and GeneChip platforms. We reported earlier the discovery of a novel prostate-abundant, androgen regulated gene, PMEPA1, which shows decreased expression in two-thirds of prostate cancer specimens analyzed thus far. Decreased PMEPA1 expression in prostatic tumors and it’s tumor cell growth in laboratory functions suggested a potential tumor suppressor gene feature of the PMEPA1. PMEPA1 protein binds to NEDD4 protein, which plays a central role in the ubiquitin-proteosome pathway. We identified the PY-motifs of the PMEPA1 protein that mediated it’s binding to NEDD4. Results: Here we report that PMEPA1 also binds to androgen receptor and that PMEPA1 may drive the degradation of AR. These findings suggested that PMEPA1 could strongly and specifically reduce the cellular levels of androgen receptor. The antagonistic function of PMEPA1 to AR is consistent with the proposed tumor suppressor role of PMEPA1. We have defined androgen responsive elements within the upstream sequences of PMEPA1 gene by using in silico regulatory model prediction strategies. Following the predictions, we validated the potential AR-binding sites by in vivo Chromatin Immunoprecipitation assays. We concluded that AR can directly bind to the PMEPA1 gene promoter and may regulate its expression. Conclusions: Taken together, we unraveled the two arms of regulatory loops in the regulation of androgen receptor by PMEPA1. This led us to propose a novel feedback loop between the potential tumor suppressor PMEPA1 and AR proteins. Thus, down-regulation of PMEPA1 in prostate cancer cells may affect increased AR levels. Further investigation of PMEPA1 in androgen receptor functions is in progress." @default.
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- W2945183048 date "2005-05-01" @default.
- W2945183048 modified "2023-09-25" @default.
- W2945183048 title "The regulation of androgen receptor levels by a feedback loop in prostate cancer cells" @default.
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