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. 1997 Apr 11;272(15):9825-32.
doi: 10.1074/jbc.272.15.9825.

Mechanism for biphasic rel A. NF-kappaB1 nuclear translocation in tumor necrosis factor alpha-stimulated hepatocytes

Y Han  1 , A R Brasier
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Mechanism for biphasic rel A. NF-kappaB1 nuclear translocation in tumor necrosis factor alpha-stimulated hepatocytes

Y Han et al. J Biol Chem. .
Free article

Abstract

The proinflammatory cytokine, tumor necrosis factor alpha (TNFalpha), is a potent activator of angiotensinogen gene transcription in hepatocytes by activation of latent nuclear factor-kappaB (NF-kappaB) DNA binding activity. In this study, we examine the kinetics of TNFalpha-activated translocation of the 65-kDa (Rel A) and 50-kDa (NF-kappaB1) NF-kappaB subunits mediated by inhibitor (IkappaB) proteolysis in HepG2 hepatoblastoma cells. HepG2 cells express the IkappaB members IkappaBalpha, IkappaBbeta, and IkappaBgamma. In response to TNFalpha, Rel A.NF-kappaB1 translocation and DNA binding activity follows a biphasic profile, with an "early" induction (15-30 min), followed by a nadir to control levels at 60 min, and a "late" induction (>120 min). The early phase of Rel A.NF-kappaB1 translocation depends on simultaneous proteolysis of both IkappaBalpha and IkappaBbeta isoforms; IkappaBgamma is inert to TNFalpha treatment. The 60-min nadir is due to a rapid IkappaBalpha resynthesis that reassociates with Rel A and completely inhibits its DNA binding activity; the 60-min nadir is not observed when IkappaBalpha resynthesis is prevented by cycloheximide treatment. By contrast, selective inhibition of IkappaBbeta proteolysis by pretreatment of HepG2 cells with the peptide aldehyde N-acetyl-Leu-Leu-norleucinal completely blocks the late phase of Rel A.NF-kappaB1 translocation. These studies indicate the presence of inducible and constitutive cytoplasmic NF-kappaB pools in hepatocytes. TNFalpha induces a coordinated proteolysis and resynthesis of IkappaB isoforms to produce dynamic changes in NF-kappaB nuclear abundance.

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