Carcinogenesis Advance Access originally published online on July 20, 2005
Carcinogenesis 2005 26(12):2086-2094; doi:10.1093/carcin/bgi187
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis Vol.26 No.12 © Oxford University Press 2005; all rights reserved.
A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes
INSERM U620, Rennes, F-35043, France; Université de Rennes 1, Rennes, F-35043, France, 1 INSERM U522, Hôpital Pontchaillou, Rennes, F-35033, France and 2 The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA
* To whom correspondence should be addressed. Tel: +33 2 23 23 44 41; Fax: +33 2 23 23 47 94; E-mail: david.gilot{at}rennes.inserm.fr
Growth factors are known to favor both proliferation and survival of hepatocytes. In the present study, we investigated if c-FLIPL (cellular FLICE-inhibitory protein, long isoform) could be involved in epidermal growth factor (EGF)-stimulated proliferation of rat hepatocytes since c-FLIPL regulates both cell proliferation and procaspase-8 maturation. Treatment with MEK inhibitors prevented induction of c-FLIPL by EGF along with total inhibition of DNA replication. However, EGF failed to inhibit processing of procaspase-8 in the presence of EGF suggesting that c-FLIPL does not play its canonical anti-apoptotic role in this model. Downregulation of c-FLIP expression using siRNA oligonucleotides strongly reduced DNA replication but did not result in enhanced apoptosis. Moreover, intermediate cleavage products of c-FLIPL and caspase-8 were found in EGF-treated hepatocytes in the absence of caspase-3 maturation and cell death. To determine whether the Fas/FADD/caspase-8/c-FLIPL complex was required for this activity, Fas, procaspase-8 and Fas-associated death domain protein (FADD) expression or function was inhibited using siRNA or constructs encoding dominant negative mutant proteins. Inhibition of any of these components of the Fas/FADD/caspase-8 pathway decreased DNA replication suggesting a function of these proteins in cell-cycle arrest. Similar results were obtained when the IETD-like caspase activity detectable in EGF-treated hepatocytes was inhibited by the pan-caspase inhibitor, z-ASP. Finally, we demonstrated co-immunoprecipitation between EGFR and Fas within 15 min following EGF stimulation. In conclusion, our results indicate that the Fas/FADD/c-FLIPL/caspase-8 pathway positively controls the G1/S transition in EGF-stimulated hepatocytes. Our data provide new insights into the mechanisms by which apoptotic proteins participate to mitogenic signals during the G1 phase.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Barbero, A. Mielgo, V. Torres, T. Teitz, D. J. Shields, D. Mikolon, M. Bogyo, D. Barila, J. M. Lahti, D. Schlaepfer, et al. Caspase-8 Association with the Focal Adhesion Complex Promotes Tumor Cell Migration and Metastasis Cancer Res., May 1, 2009; 69(9): 3755 - 3763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Shimada, M. Nakamura, S. Matsuyoshi, E. Ishida, and N. Konishi Specific positive and negative effects of FLIP on cell survival in human prostate cancer Carcinogenesis, July 1, 2006; 27(7): 1349 - 1357. [Abstract] [Full Text] [PDF]
|
|