Article thumbnail

Tumor Suppressor Pten Inhibits Nuclear Accumulation of β-Catenin and T Cell/Lymphoid Enhancer Factor 1–Mediated Transcriptional Activation

By Sujata Persad, Armelle A.Troussard, Timothy R. McPhee, David J. Mulholland and Shoukat Dedhar

Abstract

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

Topics: Original Article
Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2192018
Provided by: PubMed Central

Suggested articles

Citations

  1. (1991). A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res.
  2. (1995). Assembly and function of a TCF-alpha enhance complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.
  3. (1997). catenin is a target for the ubiquitin-proteasome pathway.
  4. (2000). Cell-cell adhesion molecules and signalling intermediates and their role in the invasive potential of prostate cancer cells.
  5. (2000). Complex cadherin expression in human prostate cancer cells.
  6. (2000). Control of beta-catenin signalling in tumor development.
  7. (2000). Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas.
  8. (1996). Functional interaction of beta-catenin with the transcription factor LEF-1.
  9. (1995). Inhibition of glycogen synthase kinase by insulin mediated by protein kinase
  10. (1995). Molecular interactions in the submembrane plaque of cell-cell and cell-matrix adhesions. Acta Anat.
  11. (1998). Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/Akt by integrin-linked kinase.
  12. (1999). Regulation of LEF-1/TCF transcription factors by Wnt and other signals.
  13. (2000). The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3 beta and cAMP-responsive element-binding proteindependent pathways.
  14. (2000). The yin-yang of TCF/beta-catenin signalling.
  15. (1996). Transcriptional control of lymphoid development: lessons from gene targeting.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.