Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 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

Drg1 was identified as a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. Its expression is associated with resistance to irinotecan (CPT-11) therapy in preclinical colorectal cancer models both in vitro and in vivo. However, the functional significance of Drg1 in these processes is unknown. We have shown for the first time that Drg1 directly binds to the BH3-only proapoptotic protein Bim. Depletion of Drg1 by small interfering RNA induced up-regulation of Bim and its accumulation in the mitochondria, which correlated with loss of mitochondrial membrane potential and induction of apoptosis in cells exposed to SN-38. Further analyses revealed that Drg1 promotes degradation of Bim through the Cullin2/ElonginB-CIS ubiquitin-protein ligase complex. Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation.
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PMID:Differentiation-related gene-1 decreases Bim stability by proteasome-mediated degradation. 1962 74

This study elucidates the role of E6-associated protein, E6-AP (a dual function steroid hormone receptor coactivator and ubiquitin-protein ligase) in the regulation of PI3K-Akt signaling pathway, prostate gland growth and proliferation. Here, we report the generation of transgenic mice and prostate cancer cell line, LNCaP cells that overexpress E6-AP protein. Using these models we show that the levels of total Akt and phosphorylated Akt (active Akt) are increased in E6-AP overexpressing prostate gland and LNCaP cells suggesting that E6-AP regulates the PI3K-Akt signaling pathway. The prostate glands in our transgenic mice are ~20% larger and produce preneoplastic lesions at the age of 18 months. Our data also suggest that E6-AP modulates PI3K-Akt signaling pathway by both androgen-independent and -dependent mechanisms. In the androgen-independent mechanism, E6-AP modulates PI3K-Akt signaling by regulating the protein levels of RhoA, a small GTPase, which is a negative regulator of the Akt signaling pathway. Further, we show that E6-AP, a known coactivator of AR, amplifies the androgen-dependent activation of PI3K-Akt signaling pathway. In addition, we show that stable overexpression of E6-AP in prostate cancer cells results in increased cell size and proliferation. Overall our data suggests that E6-AP regulates both the positive and negative modulators of the PI3K-Akt pathway in prostate cells which results in increased prostate cell growth, proliferation and decreased apoptosis.This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!
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PMID:E3 ubiquitin protein ligase, E6-associated protein (E6-AP) regulates PI3K-Akt signaling and prostate cell growth. 2082 37

E3 ubiquitin-protein ligase (HUWE1) has previously been identified as a HECT domain-containing ubiquitin ligase (E3) that is involved in several signaling pathways, transcriptional regulation, neural differentiation, DNA damage responses and apoptosis. However, the function of HUWE1 in the various types of cancer remains unclear. A previous study indicated that HUWE1 exhibited different roles depending on the cancer type due to the ubiquitination of various substrates. The objective of the present study was to determine whether HUWE1 can be employed as a prognostic indicator in human cancer. The expression of HUWE1 was examined using the Oncomine database, and gene alterations during carcinogenesis, copy number alterations and mutations of HUWE1 were then analyzed using cBioPortal, which is the International Cancer Genome Consortium and the Tumorscape database. Furthermore, the association between HUWE1 expression and patient survival was evaluated using Kaplan-Meier plotter and the PrognoScan databases. In addition, the present study attempted to establish the functional association between HUWE1 expression and cancer phenotypes, and the results revealed that HUWE1 may serve as a diagnostic marker or therapeutic target for certain types of cancer. HUWE1 may serve an oncogenic role in breast, brain and prostate cancer, while it may serve an anti-oncogenic role in colorectal cancer and certain lung cancers. The function of HUWE1 and its mechanisms require more in-depth and extensive investigation in future studies.
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PMID:Meta-analysis of gene expression alterations and clinical significance of the HECT domain-containing ubiquitin ligase HUWE1 in cancer. 3140 87