B,1 o T

to lackof inhibitionofBADby IKK. IKKphosphorylates The prevailing paradigm of how IKK regulates TNFa-induced apoptosis is the ‘‘NF-kB activation’ ’ model, in which the target(Ghosh and Karin, 2002). IKK is activated by a variety of extra-cellular stimuli, including inflammatory cytokines such as tumor necrosis factor (TNFa) (Baldwin, 2012; Liu et al., 2012). Once IKK can inhibit TNFa-induced apoptosis independently of NF-kB and, if so, what the molecular mechanism is. The BH3-only protein BAD is a member of the proapoptoticactivated, IKK phosphorylates IkBs, which are a group of cyto-plasmic inhibitors of NF-kB, on specific serines (Ser32 and BCL-2 family and plays a critical role in regulation of the mito-chondrial death machinery by extracellular stimuli (Danial andBADat serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNFa-induced apoptosis in cultured cells and increasing mortality in animals.Our results reveal that IKK inhibits TNFa-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-kB and inactivation of the proapoptotic BH3-only BAD protein