Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis.
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.
Datta
Sandeep Robert
SR
Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Ranger
Ann M
AM
Lin
Michael Z
MZ
Sturgill
James Fitzhugh
JF
Ma
Yong-Chao
YC
Cowan
Chris W
CW
Dikkes
Pieter
P
Korsmeyer
Stanley J
SJ
Greenberg
Michael E
ME
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
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