Short description
(English)
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This research proposal aims at investigating the molecular basis of TRAIL receptor- and Fas-induced apoptosis in murine and human hepatocytes, in vitro and in vivo. A specific focus will be the non-apoptotic signaling of TRAIL in primary hepatocytes leading to a modulation and acceleration of Fas-induced apoptosis in hepatocytes and liver damage. A in-depth understanding of these complex death receptor-induced signaling events in hepatocytes and tumor cells should lead to the development of strategies and drugs that can dissect apoptosis induction in tumor cells versus primary tissue cells.
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Partners and International Organizations
(English)
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AT, BE, BG, CZ, DK, FR, DE, EL, HU, IE, IT, NL, NO, PL, RO, SK, ES, SE, CH, UK
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Abstract
(English)
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TRAIL (TNF-related apoptosis-inducing ligand) is a member of the TNF family with potent apoptosis-inducing activities in tumor cells. In particular, TRAIL strongly synergizes with conventional chemotherapeutic drugs to induce tumor cell death. Thus, TRAIL has been proposed as promising future cancer therapy. Little is, however, known regarding the role of TRAIL in normal untransformed cells and whether therapeutic administration of TRAIL, alone or in combination with other apoptotic triggers, may cause tissue damage. In this study we have investigated the role of TRAIL in Fas (CD95/Apo-1)-induced hepatocyte apoptosis and liver damage. While TRAIL alone failed to induce apoptosis in isolated murine hepatocytes, it strongly amplified Fas-induced cell death. Importantly, endogenous TRAIL was found to critically regulate anti-Fas antibody induced hepatocyte apoptosis, liver damage and associated lethality in vivo. TRAIL enhanced anti-Fas-induced hepatocyte apoptosis through the activation of Jun kinase and its downstream substrate, the pro-apoptotic Bcl-2 homolog Bim. Consistently, TRAIL- or Bim-deficient mice, or wild type mice treated with a Jun kinase inhibitor, were protected against anti-Fas-induced liver damage. We conclude that TRAIL and Bim are important response modifiers of hepatocyte apoptosis and identify liver damage and lethality as a possible risk of TRAIL-based tumor therapy.
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