Regulation of Bax translocation through phosphorylation at Ser-70 of Bcl-2 by MAP kinase in NO-induced neuronal apoptosis.
The molecular mechanism of Bcl-2 phosphorylation and its relationship to Bax is largely unknown. Here we show that the phosphorylation of Bcl-2 is involved in the intracellular translocation of Bax from cytosol to mitochondria in NO-induced neuronal apoptosis. We examined how the phosphorylation of Bcl-2 is regulated during the apoptosis and found it to be mediated by the activation of p38 and ERK, members of the MAPK superfamily. Furthermore, we investigated whether Bcl-2 phosphorylation affected Bax translocation, using mutant Bcl-2 expression vectors. Cortical neuronal cells overexpressing the Bcl-2 mutant S70A (which cannot be phosphorylated) prevented the translocation of Bax. In contrast, transfection with Bcl-2 (S70D), a constitutively active Bcl-2 mutant, enhanced the translocation. Our results suggested that Bcl-2 phosphorylated at Ser-70 plays a critial role in the translocation of Bax from the cytosol to the mitochondria, and this may regulate NO-induced neuronal apoptosis.
Division of Protein Biosynthesis, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yasuyuki
Y
Ishikawa
Eiko
E
Kusaka
Yasushi
Y
Enokido
Toshihiko
T
Ikeuchi
Hiroshi
H
Hatanaka
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D010766:Phosphorylation; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases
C494826:BAX protein, human; C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases