4.8 Article

Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.0506281103

关键词

corepressor; G870A; polymorphism; cell cycle; thyroid hormone receptor beta

资金

  1. NCI NIH HHS [R01 CA099996, CA106471, R01 CA093404, CA 093404, CA 099996, T32 CA117846, R01 CA106471] Funding Source: Medline
  2. NIDDK NIH HHS [DK065264, R01 DK065264] Funding Source: Medline
  3. NIEHS NIH HHS [T32 ES007250, T32 ES07250-16, P30 ES006096, P-30-ES06096] Funding Source: Medline

向作者/读者索取更多资源

Cyclin D1 is a multifaceted regulator of both transcription and cell-cycle progression that exists in two distinct isoforms, cyclin D1a and D1b. In the prostate, cyclin D1a acts through discrete mechanisms to negatively regulate androgen receptor (AR) activity and thus limit androgen-dependent proliferation. Accordingly, cyclin D1a is rarely overexpressed in prostatic adenocarcinoma and holds little prognostic value in this tumor type. However, a common polymorphism (A870) known to facilitate production of cyclin D1b is associated with increased prostate cancer risk. Here we show that cyclin D1b is expressed at high frequency in prostate cancer and is up-regulated in neoplastic disease. Furthermore, our data demonstrate that, although cyclin D1b retains AIR association, it is selectively compromised for AIR regulation. The altered ability of cyclin D1b to regulate the AR was observed by using both in vitro and in vivo assays and was associated with compromised regulation of AIR-dependent proliferation. Consistent with previous reports, expression of cyclin D1a inhibited cell-cycle progression in AR-dependent prostate cancer cells. Strikingly, cyclin D1b significantly stimulated proliferation in this cell type. AR-negative prostate cancer cells were nonresponsive to cyclin D1 (a or b) expression, indicating that defects in AIR corepressor function yield a growth advantage specifically in AR-dependent cells. In summary, these studies indicate that the altered AR regulatory capacity of cyclin D1b contributes to its association with increased prostate cancer risk and provide evidence of cyclin D1b-mediated transcriptional regulation.

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