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| NF kappa B activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP |
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| Author(s): Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M, Janssen O, Hacker G, Dittrich-Breiholz O, Kracht M, Scheurich P, Wajant H |
| Source: JOURNAL OF CELL BIOLOGY Volume: 166 Issue: 3 Pages: 369-380 Published: AUG 2 2004 |
| Times Cited: 74 References: 55 |
| Abstract: F as (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NFkappaB via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NFkappaB signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NFkappaB was activated by overexpressed FLIPL and FLIPs in a cell type-specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NFkappaB activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NFkappaB target gene IL8. As NFkappaB signaling is inhibited during apoptosis, FasL-induced NFkappaB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NFkappaB-related response. |
| Document Type: Article |
| Language: English |
| Reprint Address: Wajant, H (reprint author), Univ Wurzburg, Med Polyclin, Dept Mol Med, Roentgenring 11, D-97070 Wurzburg, Germany |
Addresses:
1. Univ Wurzburg, Med Polyclin, Dept Mol Internal Med, D-97070 Wurzburg, Germany
2. Univ Stuttgart, Inst Cell Biol & Immunol, D-70569 Stuttgart, Germany
3. Univ Wurzburg, Sch Med, Dept Dermatol, D-97080 Wurzburg, Germany
4. Med Ctr Schlewsig Holstein, Inst Immunol, D-24105 Kiel, Germany
5. Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany
6. Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA |
| Subject Category: Cell Biology |
| IDS Number: 844ET |
| ISSN: 0021-9525 |
| DOI: 10.1083/jcb.200401036 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |