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-adrcnergic 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 FLIPL (FLICE-inhibitory protein), or the rate of I-kappa B alpha degradation, but a decrease in the Bd-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.

Sarang Z., M.P. (2005). Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. HEPATOLOGY, 42(3), 578-587 [10.1002/hep.20812].

Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice

MELINO, GENNARO;
2005

Abstract

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-adrcnergic 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 FLIPL (FLICE-inhibitory protein), or the rate of I-kappa B alpha degradation, but a decrease in the Bd-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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/11
English
Con Impact Factor ISI
alanine aminotransferase; alpha 1 adrenergic receptor; aspartate aminotransferase; caspase 8; CD4 antigen; CD8 antigen; cytochrome c; Fas antibody; Fas antigen; FLICE inhibitory protein; guanine nucleotide binding protein; I kappa B alpha; immunoglobulin enhancer binding protein; protein bcl xl; protein glutamine gamma glutamyltransferase; animal cell; animal model; animal tissue; antigen expression; apoptosis; article; cell death; cell proliferation; cell protection; controlled study; down regulation; liver cell; liver regeneration; male; mouse; nick end labeling; nonhuman; priority journal; protein cross linking; protein expression; thymocyte; transmission electron microscopy; Western blotting; Animals; Antibodies; Antigens, CD95; Apoptosis; Cell Death; Cell Division; Cell Survival; Cells, Cultured; GTP-Binding Proteins; Hepatocytes; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; T-Lymphocytes; Transglutaminases
Sarang Z., M.P. (2005). Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. HEPATOLOGY, 42(3), 578-587 [10.1002/hep.20812].
Sarang, Z; Molnar, P; Nemeth, T; Gomba, S; Kardon, T; Melino, G; Cotecchia, S; Fesus, L; Szondy, Z
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/40232
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