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Oncogene. 2001 Jul 27;20(33):4554-67.

Adhesion-regulated G1 cell cycle arrest in epithelial cells requires the downregulation of c-Myc.

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1
Department of Cell Biology, Vincent T Lombardi Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20007, USA.

Abstract

Adhesion to the extracellular matrix is required for the expression and activation of the cyclin-cyclin-dependent kinase (CDK) complexes, and for G1 phase progression of non-transformed cells. However, in non-adherent cells no molecular mechanism has yet been proposed for the cell adhesion-dependent up-regulation of the p27 cyclin-dependent kinase inhibitor (CKI), and the associated inhibition of cyclin E-CDK2. We now show that in epithelial cells the expression of c-Myc is tightly regulated by cell-substrate adhesion. When deprived of adhesion, two independently derived mammary epithelial cell lines, 184A1N4 and MCF-10A, rapidly decrease their level of c-Myc mRNA and protein. This decrease in levels of c-Myc correlates with G1 phase arrest, as indicated by hypophosphorylation of pRb and inhibition of the activity of the cyclin E-CDK2 complex. In 184A1N4 cells, cell-substrate adhesion is required for the suppression of p27, and induction of cyclin E, E2F-1, but not cyclins D1 and D3. Enforced expression of c-Myc in non-adherent 184A1N4 and MCF-10A cells reverses the adhesion-dependent inhibition of cell cycle progression. Restoration of c-Myc in non-adherent cells induces the expression of E2F-1, and hyperphosphorylation of pRb in response to EGF treatment. In addition, expression of c-Myc results in the anchorage-independent activation of the CDK2 complex, the associated upregulation of cyclin E, and the destabilization and degradation of p27 by the ubiquitin-proteasome pathway. Our study thus suggests that c-Myc is the link between cell adhesion and the regulation of p27 and cyclin E-CDK2. Furthermore, we describe a role for c-Myc in adhesion-mediated regulation of E2F-1.

PMID:
11494151
DOI:
10.1038/sj.onc.1204609
[Indexed for MEDLINE]
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