Bad is a pro-apoptotic member of the Bcl-2 family of proteins that is thought to exert a death-promoting effect by heterodimerization with Bcl-X-L, nullifying its anti-apoptotic activity. Growth factors may promote cell survival at least partially through phosphorylation of Bad at one or more of Ser-112, -136, or -155. Our previous work showed that Bad is also phosphorylated in response to cytokines at another site, which we now identify as Ser-170. The functional role of this novel phosphorylation site was assessed by site-directed mutagenesis and analysis of the pro-apoptotic function of Bad in transiently transfected HEK293 and COS-7 cells or by stable expression in the cytokine-dependent cell line, MC/9. In general, mutation of Ser-170 to Ala results in a protein with increased ability to induce apoptosis, similar to the S112A mutant. Mutation of Ser-170 to Asp, mimicking a constitutively phosphorylated site, results in a protein that is virtually unable to induce apoptosis. Similarly, the S112A/S170D double mutant does not cause apoptosis in HEK293 and MC/9 cell lines. These data strongly suggest that phosphorylation of Bad at Ser-170 is a critical event in blocking the pro-apoptotic activity of Bad.
机构:
Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Med,Div Mol Oncol, St Louis, MO 63110 USAWashington Univ, Sch Med, Howard Hughes Med Inst, Dept Med,Div Mol Oncol, St Louis, MO 63110 USA
Chao, DT
Korsmeyer, SJ
论文数: 0引用数: 0
h-index: 0
机构:Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Med,Div Mol Oncol, St Louis, MO 63110 USA
机构:
Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Med,Div Mol Oncol, St Louis, MO 63110 USAWashington Univ, Sch Med, Howard Hughes Med Inst, Dept Med,Div Mol Oncol, St Louis, MO 63110 USA
Chao, DT
Korsmeyer, SJ
论文数: 0引用数: 0
h-index: 0
机构:Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Med,Div Mol Oncol, St Louis, MO 63110 USA