Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation.
Bim is a proapoptotic, BH3-domain-only member of the Bcl-2 family that plays a role in death of trophic factor-deprived sympathetic neurons as well as in other paradigms of apoptotic death. We report here that nerve growth factor (NGF) leads to both a slow down-regulation of Bim expression in neuronal PC12 cells and rapid Bim phosphorylation. Both effects appear to be mediated by the MEK/MAPK pathway. An assay for Bim-mediated death revealed that NGF-promoted phosphorylation suppresses the proapoptotic activity of Bim. The phosphorylation sites responsible for this effect in the extra long form of rBim were identified as Ser-109 and Thr-110. Thus, NGF protects neurons from the proapoptotic effects of Bim both by acute phosphorylation and the longer term repression of expression.
Biswas
Subhas C
SC
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, 630 W 168th Street, New York, NY 10032, USA.
Greene
Lloyd A
LA
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis*; D002470:Cell Survival; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D051381:Rats; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D002352:Carrier Proteins; D018076:DNA, Complementary; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013912:Threonine; D012694:Serine; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases