title: Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis.
abstract: Growth factor suppression of apoptosis correlates with the phosphorylation and inactivation of multiple proapoptotic proteins, including the BCL-2 family member BAD. However, the physiological events required for growth factors to block cell death are not well characterized. To assess the contribution of BAD inactivation to cell survival, we generated mice with point mutations in the BAD gene that abolish BAD phosphorylation at specific sites. We show that BAD phosphorylation protects cells from the deleterious effects of apoptotic stimuli and attenuates death pathway signaling by raising the threshold at which mitochondria release cytochrome c to induce cell death. These findings establish a function for endogenous BAD phosphorylation, and elucidate a mechanism by which survival kinases block apoptosis in vivo.
authors.affiliation: Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sandeep Robert
authors.initials: SR
authors.lastname: Datta
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ranger
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Lin
authors.forename: James Fitzhugh
authors.initials: JF
authors.lastname: Sturgill
authors.forename: Yong-Chao
authors.initials: YC
authors.lastname: Ma
authors.forename: Chris W
authors.initials: CW
authors.lastname: Cowan
authors.forename: Pieter
authors.initials: P
authors.lastname: Dikkes
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein
chemical_list: C494820:Bad protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D010982:Platelet-Derived Growth Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D007334:Insulin-Like Growth Factor I