Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines.
Treatment of hepatocytes with transforming growth factor beta1 (TGF-beta1) induces growth arrest, which is followed by extensive cell death by apoptosis. Previously, we found that TGF-beta1 down-modulates nuclear factor (NF)-kappaB/Rel activity in murine B cell lymphomas, inducing apoptosis. Furthermore, p65 (RelA)-deficient mice died during gestation due to apoptosis of liver cells. Here we have explored the effects of TGF-beta1 on hepatocytes, using two untransformed murine hepatocyte cell lines, AML-12 and NMH, which constitutively express classical NF-kappaB. TGF-beta1 treatment caused increased NF-kappaB binding that was followed by a dramatic decrease in NF-kappaB levels that preceded apoptosis. Ectopic c-Rel expression ablated apoptosis induced by TGF-beta1. The down-regulation in NF-kappaB activity correlated with elevated IkappaB-alpha expression due to hypophosphorylation and increased IkappaB-alpha protein stability. Thus, NF-kappaB factor expression acts directly to promote liver cell survival. Furthermore, these findings characterize a novel signaling pathway for TGF-beta1 in epithelial cells involving down-regulation of NF-kappaB/Rel factors activity through posttranslational modification of IkappaB-alpha protein.
Arsura
M
M
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118-2394, USA.
FitzGerald
M J
MJ
Fausto
N
N
Sonenshein
G E
GE
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C497594:Relb protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051841:Transcription Factor RelB; D019311:Staurosporine