Post-transcriptional regulation of cadherin-11 expression by GSK-3 and beta-catenin in prostate and breast cancer cells

PLoS One. 2009;4(3):e4797. doi: 10.1371/journal.pone.0004797. Epub 2009 Mar 10.

Abstract

Background: The cell-cell adhesion molecule cadherin-11 is important in embryogenesis and bone morphogenesis, invasion of cancer cells, lymphangiogenesis, homing of cancer cells to bone, and rheumatoid arthritis. However, very little is known about the regulation of cadherin-11 expression.

Methodology/principal findings: Here we show that cell density and GSK-3beta regulate cadherin-11 levels in cancer cells. Inactivation of GSK3beta with lithium chloride or the GSK3 inhibitor BIO and GSK3beta knockdown with siRNA repressed cadherin-11 mRNA and protein levels. RNA Polymerase II chromatin immunoprecipitation experiments showed that inhibition of GSK3 does not affect cadherin-11 gene transcription. Although the cadherin-11 3'UTR contains putative microRNA target sites and is regulated by Dicer, its stability is not regulated by GSK3 inhibition or density. Our data show that GSK3beta regulates cadherin-11 expression in two ways: first a beta-catenin-independent regulation of cadherin-11 steady state mRNA levels, and second a beta-catenin-dependent effect on cadherin-11 3'UTR stability and protein translation.

Conclusions: Cadherin-11 mRNA and protein levels are regulated by the activity of GSK3beta and a significant degree of this regulation is exerted by the GSK3 target, beta-catenin, at the level of the cadherin-11 3'UTR.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • Breast Neoplasms / genetics*
  • Cadherins / genetics*
  • Female
  • Gene Expression Regulation*
  • Glycogen Synthase Kinase 3 / physiology*
  • Humans
  • Male
  • Prostatic Neoplasms / genetics*
  • Protein Biosynthesis
  • RNA Stability
  • RNA, Messenger / analysis
  • beta Catenin / physiology*

Substances

  • 3' Untranslated Regions
  • Cadherins
  • RNA, Messenger
  • beta Catenin
  • osteoblast cadherin
  • Glycogen Synthase Kinase 3