Androgens, acting through the androgen receptor (AR), mediate a wide spectrum of developmental and physiological processes, including the development and maintenance of the prostate. However, it has recently been shown that AR can be transcriptionally activated in vitro by 17(3-estradiol (E2) in the presence of the AR coregulator ARA70. In rodent models, neonatal exposure to exogenous estrogen results in a dose dependent alteration of adult prostate size and histology. However, targeted disruption of the estrogen receptors (ER) a and P in mice do not conclusively show a role for either ER in prostate development, potentially indicating that exogenous estrogens may be acting at least in part through AR to influence prostate growth. Estrogens and androgens are structurally similar with the major difference occurring at the C-3 position of the steroidal A-ring where dihydroxytestosterone (DHT) carries a keto group and E2 carries a phenolic hydroxyl. To investigate the amino acid residues of AR that mediate the ability of E2 to induce AR transcription, and the mechanism through which coregulators differentiate between DHT- and E2-bound AR, we propose in Specific Aim I to isolate mutations of AR that transcriptionally respond to DHT but not E2.
In Specific Aim 2, we will isolate AR mutants the preferentially respond to E2.
In Specific Aim 3, we will isolate specific coregulators that differentially interact with DHT- or E2-bound AR.
In Specific Aim 4, we will determine the mechanism of DHT or E2 induced transcription of AR in the presence of AR coregulators. Finally, in Specific Aim 5 we will determine the effect of E2 induction of AR transcription in prostate cells. The success of this proposal will not only allow us to understand how E2 regulates AR transcription, but will also provide information on transcription by AR in response to different ligands, which may ultimately lead to novel therapeutic approaches to prostate cancer.
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