Journal
HEPATOLOGY
Volume 48, Issue 6, Pages 1942-1953Publisher
WILEY
DOI: 10.1002/hep.22541
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Funding
- Bundesministerium fur Bildung and forschung
- Spemann Graduate School of Biology and Medicine of the Deutsche forschungsgemeinschaft [GSC-4]
- Australian National Health and Medical Research Council (Canberra) [257502]
- National Cancer Institute [CA80188, CA 43540]
- Leukemia and Lymphoma Society of America [7015]
- Juvenile Diabetes Research Foundation/NHMRC
- Swiss National Science Foundation
- Roche Research Foundation
- Novartis Foundations
- NATIONAL CANCER INSTITUTE [R01CA043540, R01CA080188] Funding Source: NIH RePORTER
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Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNF alpha/ActD)-induced apoptosis. Conclusion: Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction. (HEPATOLOGY 2008;48:1942-1953.)
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