Nuclear factor kappaB cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor function.
The nuclear factor-kappaB (NF-kappaB)/Rel family of transcription factors has been implicated in promoting hepatocyte survival during development and liver regeneration following partial hepatectomy. Inhibition of NF-kappaB/Rel activity by microinjection of the specific inhibitor IkappaB-alpha induces apoptosis in a nontransformed normal murine hepatocyte (NMH) cell line. Here, we demonstrate that apoptosis resulting from such inhibition requires down-regulation of the c-Myc proto-oncoprotein and occurs independently of p53 tumor suppressor function. NMH cells plated at low density displayed low sensitivity to IkappaB-alpha-induced apoptosis and high levels of c-Myc protein expression. Comicroinjection of IkappaB-alpha with the c-Myc antagonist Mad1-glutathione S-transferase fusion protein greatly enhanced cell death. In addition, transient cotransfection of low-density NMH and AML12 hepatocytes with vectors expressing IkappaB-alpha and antisense c-myc transcripts promoted cell death. Conversely, ectopic c-myc expression significantly decreased the extent of cell death in NMH cells plated at saturating density, which were characterized by very low levels of c-Myc and high susceptibility to NF-kappaB inhibition-induced cell death. Finally, IkappaB-alpha-induced apoptosis was unaffected in NMH cells expressing a dominant negative p53 protein. Thus, NF-kappaB cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor activity.
Bellas
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RE
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
Sonenshein
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GE
D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D020672:I-kappa B Proteins; D008099:Liver / Q000166:cytology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha