G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression

Nicole L. Collins, Maurico J. Reginato, Jessica K. Paulus, Dennis C. Sgroi, Joshua LaBaer, Joan S. Brugge

Research output: Contribution to journalArticle

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Abstract

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 G 1/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.

Original languageEnglish (US)
Pages (from-to)5282-5291
Number of pages10
JournalMolecular and Cellular Biology
Volume25
Issue number12
DOIs
StatePublished - Jun 2005
Externally publishedYes

Fingerprint

Anoikis
G1 Phase Cell Cycle Checkpoints
Epidermal Growth Factor
Extracellular Matrix
Cell Survival
Mimosine
Aphidicolin
Cyclin-Dependent Kinases
Cell Cycle Checkpoints
Integrins
Suspensions
Proteins
Breast
Down-Regulation
Epithelial Cells
Maintenance
Phosphorylation
Apoptosis
Neoplasm Metastasis
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. / Collins, Nicole L.; Reginato, Maurico J.; Paulus, Jessica K.; Sgroi, Dennis C.; LaBaer, Joshua; Brugge, Joan S.

In: Molecular and Cellular Biology, Vol. 25, No. 12, 06.2005, p. 5282-5291.

Research output: Contribution to journalArticle

Collins, Nicole L. ; Reginato, Maurico J. ; Paulus, Jessica K. ; Sgroi, Dennis C. ; LaBaer, Joshua ; Brugge, Joan S. / G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 12. pp. 5282-5291.
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