A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes

David Gilot*, Anne Laure Serandour, Guennady P. Ilyin, Dominique Lagadic-Gossmann, Pascal Loyer, Anne Corlu, Alexandre Coutant, Georges Baffet, Marcus E. Peter, Olivier Fardel, Christiane Guguen-Guillouzo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2086-2094
Number of pages9
JournalCarcinogenesis
Volume26
Issue number12
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Cancer Research

Fingerprint Dive into the research topics of 'A role for caspase-8 and c-FLIP<sub>L</sub> in proliferation and cell-cycle progression of primary hepatocytes'. Together they form a unique fingerprint.

Cite this