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Original Article |
Correspondence to: Shoukat Dedhar, 2660 Oak St., Vancouver, BC V6H 3Z6, Canada. Tel:(604) 875-5655 Fax:(604) 875-5452 E-mail:sdedhar{at}interchange.ubc.ca.
ß-Catenin is a protein that plays a role in intercellular adhesion as well as in the regulation of gene expression. The latter role of ß-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 ß-catenin itself. We now demonstrate that another tumor suppressor, PTEN, is also involved in the regulation of nuclear ß-catenin accumulation and T cell factor (TCF) transcriptional activation in an APC-independent manner. We show that nuclear ß-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 ß-catenin/TCF–regulated gene, is also suppressed upon reexpression of PTEN. Mechanistically, PTEN increases the phosphorylation of ß-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 ß-catenin stability, nuclear ß-catenin expression, and transcriptional activity. Our data indicate that ß-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
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