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Molecular and Cellular Biology, June 2005, p. 5282-5291, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5282-5291.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

G1/S Cell Cycle Arrest Provides Anoikis Resistance through Erk-Mediated Bim Suppression{dagger}

Nicole L. Collins,1 Maurico J. Reginato,1,{ddagger} Jessica K. Paulus,1 Dennis C. Sgroi,2 Joshua LaBaer,3 and Joan S. Brugge1*

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts,1 Department of Pathology, Harvard Medical School, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, Massachusetts,2 Harvard Institute of Proteomics, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 320 Charles Street, Cambridge, Massachusetts3

Received 8 October 2004/ Returned for modification 9 November 2004/ Accepted 15 March 2005

Proper attachment to the extracellular matrix is essential for cell survival. Detachment from the extracellular matrix results in an apoptotic process termed anoikis. Anoikis induction in MCF-10A mammary epithelial cells is due not only to loss of survival signals following integrin disengagement, but also to consequent downregulation of epidermal growth factor (EGFR) and loss of EGFR-induced survival signals. Here we demonstrate that G1/S arrest by overexpression of the cyclin-dependent kinase inhibitors p16INK4a, p21Cip1, or p27Kip1 or by treatment with mimosine or aphidicolin confers anoikis resistance in MCF-10A cells. G1/S arrest-mediated anoikis resistance involves suppression of the BH3-only protein Bim. Furthermore, in G1/S-arrested cells, Erk phosphorylation is maintained in suspension and is necessary for Bim suppression. Following G1/S arrest, known proteins upstream of Erk, including Raf and Mek, are not activated. However, retained Erk activation under conditions in which Raf and Mek activation is lost is observed, suggesting that G1/S arrest acts at the level of Erk dephosphorylation. Thus, anoikis resistance by G1/S arrest is mediated by a mechanism involving Bim suppression through maintenance of Erk activation. These results provide a novel link between cell cycle arrest and survival, and this mechanism could contribute to the survival of nonreplicating, dormant tumor cells that avert apoptosis during early stages of metastasis.

* Corresponding author. Mailing address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115. Phone: (617) 432-3974. Fax: (617) 432-3969. E-mail: joan_brugge{at}hms.harvard.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.

Molecular and Cellular Biology, June 2005, p. 5282-5291, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5282-5291.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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