Suppression of Androgen Receptor Transactivation by Akt Kinase
Abstract
Most data suggest androgen/AR may be involved in proliferation of prostate cancer, opposite roles of androgen/AR in inhibition of cell growth and apoptosis are also documented. The detailed mechanism of how androgen/AR functions in apoptosis, however, remains unclear. A serine/threonine 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 kinase/Akt pathway results in the suppression of AR target genes. Our hypothesis is that Akt may control androgen/AR-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 androgen/AR-induced cell growth inhibition and apoptosis; and 4) generate site-specific phospho-AR antibodies. Our project's success may enhance our understanding of cross-talk between Akt and androgen/AR pathway on prostate cancer progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2003
- Accession Number
- ADA415599
Entities
People
- Chawnshang Chang
Organizations
- University of Rochester