Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PMEPA1 was originally identified as a highly androgen-induced gene by serial analysis of gene expression in androgen-treated LNCaP prostate cancer (CaP) cells. PMEPA1 expression is prostate abundant and restricted to prostatic epithelial cells. PMEPA1-encoded protein shows high sequence homology to a mouse N4wbp4-encoded protein that binds to Nedd4 protein, an E3 ubiquitin-protein ligase involved in ubiquitin-dependent, proteasome-mediated protein degradation. Studies from our and other laboratories have suggested the role of PMEPA1 in cell growth regulation as noted by androgen induction of PMEPA1 expression, elevated PMEPA1 expression in nontumorigenic revertants of tumor cell lines after chromosome 8p transfer, and PMEPA1 expression alterations (up- or down-regulation) in human tumors. Here, we demonstrate that PMEPA1 protein through its PY motifs interacts with WW domains of the human NEDD4 protein. Exogenous expression of PMEPA1, in widely used CaP cell lines DU145, PC3, LNCaP, and LNCaP sublines (C4, C4-2, and C4-2B), conferred cell growth inhibition, and at least one of the PY motifs of PMEPA1 may be involved in its cell growth inhibitory functions. Quantitative expression analysis of PMEPA1 in paired normal and tumor cells of 62 patients with primary CaP revealed tumor cells associated decreased expression in 40 of 62 patients that were significantly associated with higher pathologic stage and serum prostate-specific antigen. Taken together, PMEPA1 negatively regulates growth of androgen responsive or refractory CaP cells, and these functions may be mediated through the interaction of PMEPA1 with the NEDD4 protein involved in the ubiquitin-proteasome pathway. Loss or reduced PMEPA1 expression in CaP further suggests for its role in prostate tumorigenesis.
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PMID:PMEPA1, an androgen-regulated NEDD4-binding protein, exhibits cell growth inhibitory function and decreased expression during prostate cancer progression. 1290 94

PMEPA1 was identified originally as a highly androgen-inducible gene with prostate-abundant expression that was restricted to prostatic epithelial cells. PMEPA1 protein is a NEDD4 (ubiquitin-protein isopeptide ligase)-binding protein, which negatively regulates prostate cancer cell growth. In this study we establish that PMEPA1 is a direct transcriptional target of the androgen receptor (AR). We also demonstrate that PMEPA1 negatively regulates AR protein levels in different cell culture models. Transient expression of PMEPA1 down-regulates AR protein levels and AR transcriptional targets in prostate cancer cells. Conversely, knockdown of PMEPA1 leads to elevated levels of AR protein, AR transcriptional targets (prostate-specific antigen), and increased cell cycle S phase. We define that the PMEPA1-dependent down-regulation of AR is because of AR ubiquitination and proteasome-mediated degradation. The mutant PMEPA1 (PY1/2 motif mutation) that is impaired in NEDD4 recruitment shows attenuated AR ubiquitination and AR protein down-regulation. These data support the hypothesis that PMEPA1 negatively regulates the stability of AR protein by enhancing AR ubiquitination and proteasome-mediated degradation through NEDD4. The effect of PMEPA1 on AR ubiquitination and degradation appears to be MDM2-independent. Thus, the PMEPA1-AR degradation pathway may represent a new androgen-dependent mechanism for regulating AR levels in prostate epithelial cells. These findings underscore that the decreased PMEPA1 expression frequently noted in prostate cancers may lead to increased AR functions and strengthen the biological role of PMEPA1 in prostate cancers.
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PMID:A feedback loop between the androgen receptor and a NEDD4-binding protein, PMEPA1, in prostate cancer cells. 1870 14