J Biol Chem 2002,
PMID: 12063252
Sharma, Manju; Chuang, William W; Sun, Zijie
PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin. Given the recent evidence that beta-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces beta-catenin-mediated augmentation of AR transactivation. Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta-regulated degradation of beta-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways and provide fresh insights into the mechanisms of prostate tumor development and progression.
Diseases/Pathways annotated by Medline MESH: Prostatic Neoplasms
Document information provided by NCBI PubMed
Text Mining Data
3-kinase/Akt → beta-catenin: "
Phosphatidylinositol
3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear
beta-catenin accumulation
"
Phosphatidylinositol 3-kinase/Akt → beta-catenin: "
Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation
"
beta-catenin → PTEN: "
Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta regulated degradation of beta-catenin
"
beta-catenin — GSK3beta: "
Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta regulated degradation of beta-catenin
"
Manually curated Databases
-
OpenBEL Selventa BEL large corpus:
AR
→
CTNNB1
(directlyIncreases, CTNNB1 Activity)
Evidence: Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin The activation of Akt results in the phosphorylation of a number of downstream substrates such as glycogen synthase kinase (GSK3) It has been shown that GSK3 plays an important role in the Wnt pathway by regulating the degradation of -catenin Recently, a specific protein-pro...
-
OpenBEL Selventa BEL large corpus:
GSK3B
→
GSK3B
(directlyDecreases, GSK3B Activity)
Evidence: Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin The activation of Akt results in the phosphorylation of a number of downstream substrates such as glycogen synthase kinase (GSK3) It has been shown that GSK3 plays an important role in the Wnt pathway by regulating the degradation of -catenin Recently, a specific protein-pro...
-
OpenBEL Selventa BEL large corpus:
O/5 complex ()
→
PTEN
(decreases, PTEN Activity, Activity)
Evidence: The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity.
-
OpenBEL Selventa BEL large corpus:
GSK3B
→
PTEN
(increases, PTEN Activity, GSK3B Activity)
Evidence: Modified assertion