The androgen receptor (AR) plays a central role in prostate cancer (PCa) development and progression, and appears to adapt to low levels of androgens in PCa that relapses after androgen deprivation therapy. More effective targeting of AR will require a better understanding of how its expression, stability, and activity are regulated. The AR is phosphorylated at multiple sites, and data from many groups indicate that several kinases can modulate AR activity, but it is not yet clear whether these kinases directly target AR. Moreover, it is not known how phosphorylation at specific sites regulates AR activity. As detailed in a recent report, we found that Cdk1 is an AR kinase and can enhance AR stability and responses to low levels of androgen. Our Preliminary Data further indicate that a biological function of Cdk1 may be to stabilize AR during the G2/M phase of the cell cyle. However, we do not yet know whether, or by what mechanisms, AR phosphorylation by Cdk1 regulates AR stability or functions. Therefore, my overall goals during the mentored phase of this proposal are to identify the sites on AR that are phosphorylated by Cdk1 and to determine the biological significance of phosphorylation at these sites (Aim 1). My Preliminary Studies also demonstrate that AR interacts with the catalytic subunit of protein phosphatase 1 (PP1), and that PP1 can stabilize AR and markedly enhance its transcriptional activity. Significantly, it is not yet clear whether AR is a substrate for PP1, or whether AR functions as a regulatory subunit for PP1 (which may target PP1 to chromatin and/or modulate its phosphatase activity). Moreover, the Preliminary Studies also indicate that other steroid hormone receptors similarly interact with PP1. During the mentored phase of this proposal I will initiate studies to determine whether AR is a PP1 substrate and to identify the specific sites on AR that are dephosphorylated by PP1 (Aim 2a). During the independent phase I will determine the biological function of AR phosphorylation/dephosphorylation at any identified PP1 target sites (Aim 2b) and will further explore the hypothesis that AR and other steroid receptors function to target PP1 to chromatin (Aim 3). These studies will provide new insight into how the activities of AR and other steroid receptors are regulated, and lead to new approaches for regulating these activities in steroid dependent normal tissues and cancers.
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