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Hepatology. 2002 Apr;35(4):772-8.

NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun.

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Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.


Hepatocyte resistance to tumor necrosis factor alpha (TNF)-induced apoptosis is dependent on activation of the transcription factor nuclear factor kappaB (NF-kappaB). To determine the mechanism by which NF-kappaB protects against TNF toxicity, the effect of NF-kappaB inactivation on the proapoptotic c-Jun NH(2)-terminal kinase (JNK) signaling pathway was examined in the rat hepatocyte cell line RALA255-10G. Adenovirus-mediated NF-kappaB inactivation led to a prolonged activation of JNK and increased activating protein-1 (AP-1) transcriptional activity in response to TNF treatment. Inhibition of the function of the JNK substrate and AP-1 subunit c-Jun blocked cell death from NF-kappaB inactivation and TNF as determined by measures of cell survival, numbers of apoptotic and necrotic cells, and DNA hypoploidy. Inhibition of c-Jun function blocked mitochondrial cytochrome c release and activation of caspase-3 and -7. NF-kappaB therefore blocks the TNF death pathway through down-regulation of JNK and c-Jun/AP-1. In conclusion, sustained JNK activation that occurs in the absence of NF-kappaB initiates apoptosis through a c-Jun-dependent induction of the mitochondrial death pathway.

[Indexed for MEDLINE]

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