Bcl-2 intersects the NFkappaB signalling pathway and suppresses apoptosis in ventricular myocytes

Kirshenbaum, Lorrie A.
October 2000
Clinical & Investigative Medicine;Oct2000, Vol. 23 Issue 5, p322
Academic Journal
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 NF kappa B (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 NF kappa B-dependent DNA binding and NF kappa B-directed gene transcription. No change in NF kappa B protein content was observed in myocytes expressing Bcl-2. Moreover, the Bcl-2-mediated NF kappa B activation was found to be related to changes in the activity of the NF kappa B regulatory protein I kappa B alpha (inhibitor of kappa beta). In this regard, a marked reduction in I kappa B alpha protein content was observed in ventricular myocytes expressing Bcl-2. The mode by which Bcl-2 regulates I kappa B alpha was related to the N-terminal phosphorylation and degradation of I kappa B alpha by the proteasome since an N-terminal deletion mutant of I kappa B alpha or the proteasome inhibitor lactacystin abrogated Bcl-2's inhibitory effects on I kappa B alpha and prevented NF kappa B activation. Furthermore, adenovirus-mediated delivery of a phosphorylation defective form of I kappa B alpha rendered ventricular myocytes incapable of NF kappa B activation and susceptible to tumour necrosis factor alpha-mediated apoptosis. Moreover, Bcl-2's anti-apoptotic function was lost in cells defective for NF kappa B activation. The data provide evidence for a link between Bcl-2 and the NF kappa B signalling pathway for the suppression of apoptosis in ventricular myocytes. INSET: Background: apoptosis and the cardiac myocyte.


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