It is increasingly evident that androgen receptor (AR) regulation plays a critical role in the development and progression of prostate cancer. We show that induction of cyclin D1 occurs upon ligand stimulation in androgen dependent prostatic adenocarcinoma (LNCaP) cells. Such induction results in the formation of active cyclin dependent kinase (CDK)-cyclin D1 complexes, phosphorylation of the rentinoblastoma tumor suppressor protein, and concomitant cell cycle progression. In addition, we find that cyclin D1 harbors a second cell cycle independent function responsible for restraining AR transactivation. We demonstrate that cyclin D1 co-repressor activity is extremely potent, inhibiting receptor transactivation independently of cellular background, promoter context, co-activator over expression, ligand/non-ligand activators, and cancer predisposing AR mutations/polymorphisms. Cyclin D1 binds directly to the AR N-terminus, hindering its ligand dependent transactivation function (AF-1 and AF-2). The co-repressor activity of cyclin D1 likely involves two distinct mechanisms, including the recruitment of histone deactylase (HDAC) activity and inhibition of AR N- to C- terminal interactions. These data put forth the hypothesis that cyclin D1 is a negative feedback inhibitor of the AR. Supporting this model, over expression of cyclin D1 in LNCaP (prostate cancer) cells leads to marked abrogation of cell cycle progression. Further investigation into the region(s) of cyclin D1 responsible for AR co-repression reveal a conserved central portion of the protein required for both receptor binding and inhibition. The central domain itself, elicits many of the characteristics of the wild type protein, functioning to bind HDAC3, inhibit AR transactivation, and abrogate cell cycle progression in LNCaP cells. We show that the central domain of cyclin D1 is also required for co-repression of thyroid hormone receptor beta-1 transactivation, suggesting the existence of a conserved nuclear receptor repressor motif within this region. Surprisingly, the central domain is dispensable for estrogen receptor alpha co-activation, suggesting that the co-activator and co-repressor functions of cyclin D1 are distinct and could be specifically targeted. Together, these studies provide the first in-depth analysis of AR co-repressor function, identifying the mechanism of cyclin D1 action and potentially leading to the discovery of novel therapeutic targets for the treatment of prostate cancer.
|School:||University of Cincinnati|
|Department:||Cell and Molecular Biology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Androgen receptor, Cell cycle, Co-repressor, Hormone, Prostate cancer, Transciption|
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