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J. Biol. Chem., Vol. 277, Issue 41, 38676-38682, October 11, 2002

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IKK Is Required for Bcl-2-mediated NF-B Activation in Ventricular Myocytes^*

Kelly M. Regula, Karen Ens, and Lorrie A. Kirshenbaum^§

From the Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and the Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada

The transcription factor nuclear factor B (NF-B) is regulated by cytoplasmic inhibitor IB. An integral step in the activation of NF-B involves the phosphorylation and degradation of IB. We have previously reported that IB activity is diminished in ventricular myocytes expressing Bcl-2 (de Moissac, D., Zheng, H., and Kirshenbaum, L. A. (1999) J. Biol. Chem. 274, 29505-29509). The underlying mechanism by which Bcl-2 activates NF-B is undefined. In view of growing evidence that the IB kinases (IKKs), notably IKK, are involved in signal induced phosphorylation of IB, we ascertained whether IKK is necessary and sufficient for Bcl-2 mediated NF-B activation. Here we demonstrate that expression of Bcl-2 in ventricular myocytes resulted in an increase in NF-B-dependent DNA binding, NF-B gene transcription and reduced IB levels. An increase in the IKK kinase activity was observed in cells expressing full-length Bcl-2 but not in cells expressing the BH4 deletion mutant of Bcl-2 (BH4; residues 10-30). Catalytically inactive mutants of IKK, but not IKK, suppressed Bcl-2-mediated IB phosphorylation and NF-B activation. Transfection of human embryonic 293 cells with a kinase-defective Raf-1 or a kinase-defective mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEKK-1) suppressed Bcl-2-mediated IKK activity and NF-B activation. Further, Bcl-2-mediated NF-B activity was impaired in nullizygous mouse embryonic fibroblasts deficient for IKK. In this report, we provide the first direct evidence that Bcl-2 activates NF-B by a signaling mechanism that involves Raf-1/MEKK-1 mediated activation of IKK.

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