Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity.
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.
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Thomas R
TR
Salas
Jeri
J
Kim
Funda
F
Vakar-Lopez
Anita L
AL
Sabichi
Patricia
P
Troncoso
Guido
G
Jenster
Akira
A
Kikuchi
Shao-Yong
SY
Chen
Lirim
L
Shemshedini
Milind
M
Suraokar
Christopher J
CJ
Logothetis
John
J
DiGiovanni
Scott M
SM
Lippman
David G
DG
Menter
D059002:Androgen Receptor Antagonists; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection
D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3