Bcl-2 intersects the NFkappaB signalling pathway and suppresses apoptosis in ventricular myocytes.
As a first step toward identifying putative regulators of apoptosis in the heart, the impact of the anti-apoptosis protein Bcl-2 (B-cell lymphoma gene) on the NFkappaB (nuclear factor kappa beta) signalling pathway in suppressing apoptosis in ventricular myocytes was studied. The data indicate that adenovirus-mediated delivery of Bcl-2 resulted in a significant increase in NFkappaB-dependent DNA binding and NFkappaB-directed gene transcription. No change in NFkappaB protein content was observed in myocytes expressing Bcl-2. Moreover, the Bcl-2-mediated NFkappaB activation was found to be related to changes in the activity of the NFkappaB regulatory protein IkappaBalpha (inhibitor of kappa beta). In this regard, a marked reduction in IkappaBalpha protein content was observed in ventricular myocytes expressing Bcl-2. The mode by which Bcl-2 regulates IkappaBalpha was related to the N-terminal phosphorylation and degradation of IkappaBalpha by the proteasome since an N-terminal deletion mutant of IkappaBalpha or the proteasome inhibitor lactacystin abrogated Bcl-2's inhibitory effects on IkappaBalpha and prevented NFkappaB activation. Furthermore, adenovirus-mediated delivery of a phosphorylation defective form of IkappaBalpha rendered ventricular myocytes incapable of NFkappaB activation and susceptible to tumour necrosis factor alpha-mediated apoptosis. Moreover, Bcl-2's anti-apoptotic function was lost in cells defective for NFkappaB activation. The data provide evidence for a link between Bcl-2 and the NFkappaB signalling pathway for the suppression of apoptosis in ventricular myocytes.
Kirshenbaum
L A
LA
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and the Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg. Lorrie@sbrc.umanitoba.ca
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha