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Degree

PhD, University of Cincinnati, Medicine : Cell & Molecular Biology, 2006.

Abstract

The role of androgens in the prostate is clear, as activation of the androgen receptor (AR) is critical for development, survival, and function of this organ. Moreover, AR activity is necessary for the growth and survival of prostatic cancers and is the primary target of non-organ confined tumors. Unfortunately, androgen ablation therapy is ultimately circumvented by restoration of AR activity, therefore providing the impetus to understand the factors which govern androgen-dependent growth. Cyclin D1 plays a multifaceted role in the prostate in that it is a key regulator of both the AR and molecules controlling cellular proliferation. Hence, it exists as a positive and negative regulator of androgen dependent growth. Herein, we show that cyclin D1 utilizes at least two distinct mechanisms as a potent inhibitor of AR function in the context of prostatic cancer. First, cyclin d1 interacts with histone deacetylase 3 and utilizes its enzymatic activity to elicit repression. Second, cyclin D1 interacts with an important regulatory domain in the amino terminus of the AR to preclude changes required for receptor activity. We demonstrate these cyclin D1 co-modifier functions are contained within a central region of the protein termed the repressor domain (RD) and that this region is sufficient to inhibit androgen dependent proliferation in prostate cancer. Furthermore, we reveal that deregulation of these cyclin D1 functions has clinical implications to prostate cancer, as a splice variant of cyclin D1, termed cyclin D1b, is highly expressed in prostate tumors. While cyclin D1b retains some transcriptional coregulatory functions, its ability to repress certain AR targets is compromised. The biological consequence of this defect is it fails to limit androgen dependent growth. In fact, ectopic expression of cyclin D1b increased proliferation in an androgen dependent prostate cancer cell line. Together, these data demonstrate a functional role for cyclin D1 in regulating AR activity and provide evidence of altered regulation in the development of prostate cancer. It further demonstrates a complex role of cyclin D1 as a rheostat for prostatic growth

Keywords

prostate cancer; androgen receptor; cyclin d1

Advisor

Dr. Karen E Knudsen

Pages

150p.

Document number: ucin1147967238
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1147967238

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