Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is widely suspected that androgen-independent prostate cancer growth depends on androgen receptor signaling via ill-defined mechanisms. Prostate-specific antigen (PSA) expression is often used to measure androgen receptor activity in cells and prostate cancer progression in patients. In the present study, we have compared androgen receptor activity using PSA and human male germ cell-associated kinase (hMAK), as read-outs in androgen-dependent LNCaP and androgen-independent C4-2B cells. As expected, very little PSA and hMAK expression were detected in LNCaP cells in the absence of androgens, whereas substantial expression of PSA was observed only in C4-2B cells under the same conditions. The addition of dihydrotestosterone to the culture medium increased the expression of both genes in both cell types. Comprehensive chromatin immunoprecipitation analysis of the entire PSA locus and an androgen-response element in hMAK unexpectedly revealed that androgen receptor was not occupying any site in the absence of dihydrotestosterone in either cell type. In line with the expression data, and in the absence of dihydrotestosterone, histone acetylation and RNA polymerase II occupancy was substantial at the PSA locus in C4-2B but not in LNCaP cells. In the presence of dihydrotestosterone, androgen receptor was found to occupy mainly the enhancer region of PSA in both cell types, accompanied with increases in histone acetylation and RNA polymerase II occupancy. Although the androgen receptor was not directly involved in the androgen-independent expression of PSA in C4-2B cells, small interfering RNA knock-down of androgen receptor significantly reduced PSA expression in both the presence and absence of dihydrotestosterone. In contrast, hMAK expression was decreased only in the presence of dihydrotestosterone after androgen receptor knock-down. We conclude that androgen-independent expression of PSA in C4-2B cells does not rely on the direct occupancy of the androgen receptor at the PSA locus, but is nevertheless affected indirectly via unknown androgen receptor-dependent mechanism(s) that influence the expression from some but not all androgen receptor target genes.
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PMID:Androgen receptor-dependent PSA expression in androgen-independent prostate cancer cells does not involve androgen receptor occupancy of the PSA locus. 1614 Sep 73

Androgen receptor (AR) is a ligand-induced transcriptional factor, which plays an important role in the normal development of prostate as well as in the progression of prostate cancer. Numerous coactivators, which associate with AR and function to remodel chromatin and recruit RNA polymerase II to enhance the transcriptional potential of AR, have been identified. Among these coactivators, few are protein kinases. In this study, we describe the characterization of a novel protein kinase, male germ cell-associated kinase (MAK), which serves as a coactivator of AR. We present evidence, which indicates that (a) MAK physically associates with AR (MAK and AR are found to be coprecipitated from cell extracts, colocalized in nucleus, and corecruited to prostate-specific antigen promoter in LNCaP as well as in transfected cells); (b) MAK is able to enhance AR transactivation potential in an androgen- and kinase-dependent manner in several prostate cancer cells and synergize with ACTR/steroid receptor coactivator-3 coactivator; (c) small hairpin RNA (shRNA) knocks down MAK expression resulting in the reduction of AR transactivation ability; (d) MAK-shRNA or kinase-dead mutant, when introduced into LNCaP cells, reduces the growth of the cells; and (e) microarray analysis of LNCaP cells carrying kinase-dead MAK mutant showed a significant impediment of AR signaling, indicating that endogenous MAK plays a general role in AR function in prostate cancer cells and likely to be a general coactivator of AR in prostate tissues. The highly restricted expression of this kinase makes it a potentially useful target for intervention of androgen independence.
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PMID:Male germ cell-associated kinase, a male-specific kinase regulated by androgen, is a coactivator of androgen receptor in prostate cancer cells. 1695 Nov 54