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J Biol Chem. 1998 Sep 11;273(37):23946-51.

Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha.

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The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6.


Nuclear factor kappaB (NFkappaB) is a ubiquitously expressed transcription factor that is regulated by the cytoplasmic inhibitor protein IkappaBalpha. Biological agents such as tumor necrosis factor alpha (TNFalpha), which activate NFkappaB, result in the rapid degradation of IkappaBalpha. Adenoviral-mediated gene transfer of Bcl-2 prevents apoptosis of neonatal ventricular myocytes induced by TNFalpha. In view of the growing evidence that NFkappaB may play an important role in regulating apoptosis, we determined whether TNFalpha and Bcl-2 could modulate the activity of NFkappaB in ventricular myocytes. Stimulation of myocytes with TNFalpha resulted in a 2.1-fold increase (p < 0.001) in NFkappaB-dependent gene transcription and nuclear DNA binding. Similarly, a 1.9-fold increase (p < 0.0002) in NFkappaB-dependent gene transcription was observed in myocytes expressing Bcl-2. Nuclear DNA binding activity of NFkappaB was significantly increased in myocytes expressing Bcl-2, with a concomitant reduction in IkappaBalpha protein level. The Bcl-2-mediated loss of IkappaBalpha could be prevented by the proteasome inhibitor lactacystin, consistent with the notion that the targeted degradation of IkappaBalpha consequent to overexpression of Bcl-2 utilizes the ubiquitin-proteasome pathway. This was further tested in human 293 cells in which the N-terminal region of IkappaBalpha was identified to be an important regulatory site for Bcl-2. Deletion of this region or a serine to alanine substitution mutant at amino acids 32 and 36, which are defective for both phosphorylation and degradation, were more resistant than wild type IkappaBalpha to the inhibitory effects of Bcl-2. To our knowledge, this provides the first evidence for the regulation of IkappaBalpha by Bcl-2 and suggests a link between Bcl-2 and the NFkappaB signaling pathway in the suppression of apoptosis.

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