Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation.
beta-Catenin is a protein that plays a role in intercellular adhesion as well as in the regulation of gene expression. The latter role of beta-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 beta-catenin itself. We now demonstrate that another tumor suppressor, PTEN, is also involved in the regulation of nuclear beta-catenin accumulation and T cell factor (TCF) transcriptional activation in an APC-independent manner. We show that nuclear beta-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 beta-catenin/TCF-regulated gene, is also suppressed upon reexpression of PTEN. Mechanistically, PTEN increases the phosphorylation of beta-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 beta-catenin stability, nuclear beta-catenin expression, and transcriptional activity. Our data indicate that beta-catenin/TCF-mediated gene transcription is regulated by PTEN, and this may represent a key mechanism by which PTEN suppresses tumor progression.
Persad
S
S
British Columbia Cancer Agency, Jack Bell Research Center, Vancouver V6H 3Z6, British Columbia, Canada.
Troussard
A A
AA
McPhee
T R
TR
Mulholland
D J
DJ
Dedhar
S
S
D015820:Cadherins / Q000096:biosynthesis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D016384:Consensus Sequence; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D009841:Oligonucleotides; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000099200:Scaffold Protein ILK
D015820:Cadherins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019938:Cyclin D1; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D051821:Lymphoid Enhancer-Binding Factor 1; D009841:Oligonucleotides; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C495270:CTNNB1 protein, human; C494929:PTEN protein, human