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First published online January 10, 2008
doi: 10.1242/10.1242/jcs.017012

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

Alaina K. Fournier¹, Latoya E. Campbell¹, Paola Castagnino¹, Wendy F. Liu², Betty M. Chung¹, Valerie M. Weaver^3,*, Christopher S. Chen² and Richard K. Assoian^1,

¹ Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA
² Department of Bioengineering, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA
³ Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA

Author for correspondence (e-mail: rka{at}pharm.med.upenn.edu)

Accepted 25 October 2007

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.

Key words: G1 phase, Cell cycle, Proliferation

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