Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion.
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.
Fournier
Alaina K
AK
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
Campbell
Latoya E
LE
Castagnino
Paola
P
Liu
Wendy F
WF
Chung
Betty M
BM
Weaver
Valerie M
VM
Chen
Christopher S
CS
Assoian
Richard K
RK
D015820:Cadherins / Q000096:biosynthesis*; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000096:biosynthesis*; D008954:Models, Biological; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
C493956:CDKN1A protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016023:Integrins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020744:rac GTP-Binding Proteins