|
|
|
|
|
|
|
||
© The Rockefeller University Press,
0021-9525/2001//1161 $5.00
The Journal of Cell Biology, Volume 153, Number 6,
, 2001 1161-1174
Original Article |
Tumor Suppressor Pten Inhibits Nuclear Accumulation of β-Catenin and T Cell/Lymphoid Enhancer Factor 1–Mediated Transcriptional Activation
sdedhar{at}interchange.ubc.ca
β-Catenin is a protein that plays a role in intercellular adhesion as well as in the regulation of gene expression. The latter role of β-catenin is associated with its oncogenic properties due to the loss of expression or inactivation of the tumor suppressor adenomatous polyposis coli (APC) or mutations in β-catenin itself. We now demonstrate that another tumor suppressor, PTEN, is also involved in the regulation of nuclear β-catenin accumulation and T cell factor (TCF) transcriptional activation in an APC-independent manner. We show that nuclear β-catenin expression is constitutively elevated in PTEN null cells and this elevated expression is reduced upon reexpression of PTEN. TCF promoter/luciferase reporter assays and gel mobility shift analysis demonstrate that PTEN also suppresses TCF transcriptional activity. Furthermore, the constitutively elevated expression of cyclin D1, a β-catenin/TCF–regulated gene, is also suppressed upon reexpression of PTEN. Mechanistically, PTEN increases the phosphorylation of β-catenin and enhances its rate of degradation. We define a pathway that involves mainly integrin-linked kinase and glycogen synthase kinase 3 in the PTEN-dependent regulation of β-catenin stability, nuclear β-catenin expression, and transcriptional activity. Our data indicate that β-catenin/TCF–mediated gene transcription is regulated by PTEN, and this may represent a key mechanism by which PTEN suppresses tumor progression.
Key Words: integrin-linked kinase • glycogen synthase kinase 3 • cyclin D1 • prostate cancer • protein kinase B
© 2001 The Rockefeller University Press
Abbreviations used in this paper: APC, adenomatous polyposis coli; CDK, cyclin-dependent kinase; GFP, green fluorescent protein; GSK-3, glycogen synthase kinase 3; HA, hemagglutinin; ILK, integrin-linked kinase; KD, kinase deficient; LEF, lymphoid enhancer factor; PI-3, phosphatidylinositol 3; PKB, protein kinase B; TCF, T cell factor; WT, wild-type.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
|
|
