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Papers In Press, published online ahead of print May 18, 2006
Lab. Memb. Biochem. Biophys., National Inst. Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892-9410
Corresponding Author: bjs{at}mail.nih.gov
Mitochondrial translocation of proapoptotic Bax prior to apoptosis is well-established after treatment with many cell death stimulants or under apoptosis-inducing conditions. The mechanism of mitochondrial translocation of Bax is, however, still unknown. The aim of current research is to investigate the mechanism of Bax activation and mitochondrial translocation to initiate apoptosis in human hepatoma HepG2 and porcine kidney LLC-PK1 cells exposed to various cell death agonists. Phosphorylation of Bax by staurosporine, H2O2, etoposide, and UV exposure by stress-activated JNK and p38 kinase, was demonstrated by the shift in the pI value of Bax on 2-D gels and confirmed by metabolic labeling with [32P]-inorganic phosphate in HepG2 cells. Specific inhibitors of JNK and p38 kinase significantly inhibited Bax phosphorylation, mitochondrial translocation of Bax, and apoptosis in HepG2 cells. A specific siRNA to mitogen activated protein kinase kinase isoform 4 (MAPKK4), upstream kinase of JNK and p38 kinase, markedly decreased the levels of MAPKK4 and MAPKK3/6, blocked the activation of JNK or p38 kinase, and inhibited Bax phosphorylation. In contrast, the negative control siRNA did not cause these changes. Confocal microscopy of various Bax mutants showed differential rates of mitochondrial translocation of Bax before and after STS treatment. Among the Bax mutants, Thr167Asp mutant did not translocate to mitochondria after STS exposure, suggesting that Thr167 is a potential phosphorylation site. In conclusion, our current results demonstrate, for the first time, that Bax is phosphorylated by stress-activated JNK and/or p38 kinase and that phosphorylation of Bax leads to mitochondrial translocation prior to apoptosis.
J. Biol. Chem, 10.1074/jbc.M510644200
Submitted on September 29, 2005
Accepted on May 18, 2006
JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation, mitochondrial translocation and apoptosis of human hepatoma HepG2 cells
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