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Molecular and Cellular Biology, August 2004, p. 7072-7081, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7072-7081.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Keratins Modulate c-Flip/Extracellular Signal-Regulated Kinase 1 and 2 Antiapoptotic Signaling in Simple Epithelial Cells

Stéphane Gilbert,1,2 Anne Loranger,2 and Normand Marceau1,2*

Centre de Recherche en Cancérologie et Département de Médecine, Université Laval,1 Centre de Recherche de L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada2

Received 28 October 2003/ Returned for modification 16 December 2003/ Accepted 24 May 2004

Among the large family of intermediate filament proteins, the keratin 8 and 18 (K8/K18) pair constitutes a hallmark for all simple epithelial cells, such as hepatocytes and mammary cells. Functional studies with different cell models have suggested that K8/K18 are involved in simple epithelial cell resistance to several forms of stress that may lead to cell death. We have reported recently that K8/K18-deprived hepatocytes from K8-null mice are more sensitive to Fas-mediated apoptosis. Here we show that upon Fas, tumor necrosis factor alpha receptor, or tumor necrosis factor alpha-related apoptosis-inducing ligand receptor stimulation, an inhibition of extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation sensitizes wild-type but not K8-null mouse hepatocytes to apoptosis and that a much weaker ERK1/2 activation occurs in K8-null hepatocytes. In turn, this impaired ERK1/2 activation in K8-null hepatocytes is associated with a drastic reduction in c-Flip protein, an event that also holds in a K8-null mouse mammary cell line. c-Flip, along with Raf-1, is part of a K8/K18-immunoisolated complex from wild-type hepatocytes, and Fas stimulation leads to further c-Flip and Raf-1 recruitment in the complex. This points to a new regulatory role of simple epithelium keratins in the c-Flip/ERK1/2 antiapoptotic signaling pathway.

* Corresponding author. Mailing address: Centre de Recherche HDQ, 9 McMahon, Québec G1R 2J6, Canada. Phone: (418) 525-4444, ext. 15559. Fax: (418) 691-5439. E-mail: normand.marceau{at}crhdq.ulaval.ca.

Molecular and Cellular Biology, August 2004, p. 7072-7081, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7072-7081.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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