Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity Article (Faculty180)

cited authors

  • Salas, Thomas R; Kim, Jeri; Vakar-Lopez, Funda; Sabichi, Anita L; Troncoso, Patricia; Jenster, Guido; Kikuchi, Akira; Chen, Shao- Y; Shemshedini, Lirim; Suraokar, Milind; Logothetis, Christopher J; DiGiovanni, John; Lippman, Scott M; Menter, David G

description

  • Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligand-binding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3 beta. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3 beta. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3 beta affected the ability of these mutants to co-distribute with the androgen receptor in the cell nucleus, also that both glycogen synthase kinase-3beta and androgen receptor proteins can be found in cell nuclei of prostate cancer tissue samples. Because glycogen synthase kinase-3 beta activity is suppressed after the enzyme is phosphorylated by protein kinase B/Akt and Akt activity frequently increases during the progression of prostate cancer, nullification of the glycogen synthase kinase-3 beta-mediated suppression of androgen receptor activity by Akt likely contributes to prostate cancer progression.

authors

publication date

  • 2004

published in

start page

  • 19191

end page

  • 200

volume

  • 279