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...
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Veröffentlicht in: | The international journal of biochemistry & cell biology 2008, Vol.40 (9), p.1861-1871 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 1357-2725 |
DOI: | 10.1016/j.biocel.2008.01.029 |