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Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas‐mediated cell death in mice
Author(s) -
Sarang Zsolt,
Molnár Péter,
Németh Tamás,
Gomba Szabolcs,
Kardon Tamás,
Melino Gerry,
Cotecchia Susanna,
Fésüs László,
Szondy Zsuzsa
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20812
Subject(s) - fas ligand , tissue transglutaminase , apoptosis , programmed cell death , biology , signal transduction , hepatocyte , receptor , in vivo , microbiology and biotechnology , medicine , endocrinology , cancer research , in vitro , enzyme , biochemistry
Tissue transglutaminase (TG2) is a protein cross‐linking enzyme known to be expressed by hepatocytes and to be induced during the in vivo hepatic apoptosis program. TG2 is also a G protein that mediates intracellular signaling by the alpha‐1b‐adrenergic receptor (AR) in liver cells. Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti‐Fas antibodies to mice causes both disseminated endothelial cell apoptosis and fulminant hepatic failure. Here we report that an intraperitoneal dose of anti‐Fas antibodies, which is sublethal for wild‐type mice, kills all the TG2 knock‐out mice within 20 hours. Although TG2 −/− thymocytes exposed to anti‐Fas antibodies die at the same rate as wild‐type mice, TG2 −/− hepatocytes show increased sensitivity toward anti‐Fas treatment both in vivo and in vitro, with no change in their cell surface expression of Fas, levels of FLIP L (FLICE‐inhibitory protein), or the rate of I‐κBα degradation, but a decrease in the Bcl‐x L expression. We provide evidence that this is the consequence of the impaired AR signaling that normally regulates the levels of Bcl‐x L in the liver. In conclusion , our data suggest the involvement of adrenergic signaling pathways in the hepatic regeneration program, in which Fas ligand‐induced hepatocyte proliferation with a simultaneous inhibition of the Fas‐death pathway plays a determinant role. (H EPATOLOGY 2005.)