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Suppression of Androgen Receptor Transactivation by Akt Kinase

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Annual rept. 1 Jan-31 Dec 2002

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Most data suggest androgenAR may be involved in proliferation of prostate cancer, opposite roles of androgenAR in inhibition of cell growth and apoptosis are also documented. The detailed mechanism of how androgenAR functions in apoptosis, however, remains unclear. A serinethreonine kinase Akt was demonstrated to play a role in promoting cell survival with anti-apoptotic effects. Akt was also found to be constitutively active in prostate cancer LNCaP cells and play an essential role for LNCaP survival. Our preliminary data demonstrated that Akt phosphorylates the androgen receptor AR at Ser210 and Ser790. A mutation at AR Ser210 results in reversion of Akt-mediated suppression of AR transactivation. Activation of phosphatidylinositol-3-OH kinaseAkt pathway results in the suppression of AR target genes. Our hypothesis is that Akt may control androgenAR-induced apoptosis by phosphorylating and inhibiting AR. Our aims are to 1 prove that Akt can promote AR degradation via phosphorylation of AR in vivo 2 dissect the molecular mechanism by which Akt promotes AR protein degradation 3 determine whether Akt can suppress androgenAR-induced cell growth inhibition and apoptosis and 4 generate site-specific phospho-AR antibodies. Our projects success may enhance our understanding of cross-talk between Akt and androgenAR pathway on prostate cancer progression.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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