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Nuclear Factor B Cooperates with c-Myc in Promoting Murine Hepatocyte Survival in a Manner Independentof p53 Tumor Suppressor Function¹

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

The nuclear factor-B (NF-B)/Rel family of transcription factors has been implicated in promoting hepatocyte survival during development and liver regeneration following partial hepatectomy. Inhibition of NF-B/Rel activity by microinjection of the specific inhibitor IB- 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 IB--induced apoptosis and high levels of c-Myc protein expression. Comicroinjection of IB- 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 IB- 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-B inhibition-induced cell death. Finally, IB--induced apoptosis was unaffected in NMH cells expressing a dominant negative p53 protein. Thus, NF-B cooperates with c-Myc in promoting murine hepatocyte survival in a manner independent of p53 tumor suppressor activity.

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