Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion

J Cell Sci. 2008 Jan 15;121(Pt 2):226-33. doi: 10.1242/jcs.017012.

Abstract

Integrin-mediated adhesion to substratum is required for cyclin D1 induction in mesenchymal cells, but we show here that the induction of cyclin D1 persists despite blockade of ECM-integrin signaling in MCF10A mammary epithelial cells. E-cadherin-mediated cell-cell adhesion also supports cyclin D1 induction in these cells, and the combined inhibition of both E-cadherin and integrin adhesion is required to prevent the expression of cyclin D1 mRNA and protein. Our previous studies described a pro-proliferative effect of E-cadherin in MCF10A cells, mediated by Rac, and we now show that Rac is required for cyclin D1 mRNA induction by both E-cadherin and integrin engagement. The levels of p21Cip1 and p27Kip1, Cdk inhibitors that are also targets of integrin signaling, are not affected by E-cadherin-mediated cell-cell adhesion. Finally, we show that the increased expression of cyclin D1 mRNA associated with E-cadherin-dependent cell-cell adhesion is causally linked to an increased entry into S phase. Our results identify Rac signaling to cyclin D1 as a crucial pro-proliferative effect of E-cadherin-mediated cell-cell adhesion.

Publication types

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

MeSH terms

  • Cadherins / biosynthesis*
  • Cell Adhesion
  • Cell Communication
  • Cell Line, Tumor
  • Cyclin D1 / biosynthesis*
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis
  • Gene Expression Regulation*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Integrins / biosynthesis*
  • Models, Biological
  • Signal Transduction
  • rac GTP-Binding Proteins / metabolism*

Substances

  • CDKN1A protein, human
  • Cadherins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Integrins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • rac GTP-Binding Proteins