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Gi and RGS proteins provide biochemical control of androgen receptor nuclear exclusion
Authors:Avi Rimler  Ralf Jockers  Zipora Lupowitz  Nava Zisapel
Affiliation:(1) Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel;(2) Institut National de la Santé et de la Recherche Médicale (INSERM) U. 567, Centre National de la Recherche Scientifique (CNRS) UMR 8104 and Universite Paris V, Institut Cochin, Department of Cell Biology, F-75014 Paris, France
Abstract:
Nuclear localization of androgen receptors (ARs) is essential for their activity. Melatonin induces AR nuclear exclusion via increase in cGMP, calcium, and protein kinase C (PKC) activation, presumably through G-protein(s). The effects of regulators of G-protein signaling (RGS) on AR localization were studied in AR-expressing PC3 cells. Gi-specific RGS10 inhibited melatonin but not cGMP-induced AR nuclear exclusion, independent of androgen. No evidence for Gq activation by melatonin was found. However, Gi/Gq-selective RGS4 inhibited AR nuclear exclusion downstream of PKC activation—an effect that was abrogated by constitutively active Gq. RGS10 and RGS4, but not RGS2, ablated the inhibitory effects of melatonin on AR reporter gene activity. For the first time, these data show regulation by Gi and Gi-specific RGS protein-mediated AR nuclear exclusion, which is potentially important in the treatment of AR-dependent cancers and neurodegenerative disorders. They also reveal a role for a Gq protein downstream of PKC activation in AR nuclear localization.
Keywords:RGS10  RGS4  RGS2  androgen receptor  nuclear localization  PKC  calcium  melatonin  cGMP
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