Beta-catenin triggers nuclear factor kappaB-dependent up-regulation of hepatocyte inducible nitric oxide synthase.
Disruption of cell-to-cell contacts, as observed in many pathophysiological conditions, prime hepatocytes for compensatory hyperplastic response that involves induction of several genes, including proto-oncogenes and other gene targets of beta-catenin signaling pathway. By using cultured hepatocytes and experimental models of adherens junction disruption we have investigated changes in beta-catenin subcellular localization and their relationships with inducible nitric oxide synthase (iNOS) expression. Two experimental models were employed: (a) rat hepatocytes obtained by collagenase liver perfusion within the first 48 h of culture; (b) 48-h old cultured hepatocytes, transiently transfected or not with a plasmid encoding for dominant/negative inhibitory kappa B-alpha, exposed to ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'-tetraacetic acid/LiCl treatment. beta-Catenin signaling and cellular localization, iNOS expression and nuclear factor kappaB involvement, were investigated using morphological, cell and molecular biology techniques. E-cadherin-mediated disruption of cell-to-cell contacts induces early beta-catenin translocation from membrane to cytoplasm and nuclear compartments, events that are followed by up-regulation of c-myc, cyclin D1 and beta-transducin repeat-containing protein expression. This, in turn, resulted eventually in iNOS induction that was mechanistically related to nuclear factor kappaB activation, as unequivocally shown in cells expressing dominant negative inhibitory kappa B-alpha. Our data indicate that E-cadherin disassembly and concomitant inactivation of glycogen synthase kinase-3beta result in nuclear factor kappaB-dependent induction of iNOS in hepatocytes.
Bandino
Andrea
A
Dipartimento di Medicina e Oncologia Sperimentale, University of Torino, Torino, Italy.
Compagnone
Alessandra
A
Bravoco
Vittoria
V
Cravanzola
Carlo
C
Lomartire
Anna
A
Rossetto
Chiara
C
Novo
Erica
E
Cannito
Stefania
S
Valfrè di Bonzo
Lorenzo
L
Zamara
Elena
E
Autelli
Riccardo
R
Parola
Maurizio
M
Colombatto
Sebastiano
S
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D002450:Cell Communication; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D015203:Reproducibility of Results; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
D015820:Cadherins; D016328:NF-kappa B; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D004533:Egtazic Acid; D052247:Nitric Oxide Synthase Type II; D018021:Lithium Chloride