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 contributi...

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Bibliographic Details
Published in:Developmental cell 2002-11, Vol.3 (5), p.631-643
Main Authors: Datta, Sandeep Robert, Ranger, Ann M., Lin, Michael Z., Sturgill, James Fitzhugh, Ma, Yong-Chao, Cowan, Chris W., Dikkes, Pieter, Korsmeyer, Stanley J., Greenberg, Michael E.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
B-Lymphocytes - cytology
bcl-Associated Death Protein
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Differentiation
Cell Survival
Cells, Cultured
Cytochrome c Group - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - immunology
Insulin-Like Growth Factor I - pharmacology
Mice
Mice, Inbred C57BL
Mitochondria - metabolism
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Phosphorylation
Platelet-Derived Growth Factor - pharmacology
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Signal Transduction
T-Lymphocytes - cytology
Thymus Gland - cytology
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary: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.
ISSN:1534-5807
1878-1551
DOI:10.1016/S1534-5807(02)00326-X