Abstract
Bag1 is a cochaperone for the heat-shock protein Hsp70 that interacts with C-Raf, B-Raf, Akt, Bcl-2, steroid hormone receptors and other proteins. Here we use targeted gene disruption in mice to show that Bag1 has an essential role in the survival of differentiating neurons and hematopoietic cells. Cells of the fetal liver and developing nervous system in Bag1-/- mice underwent massive apoptosis. Lack of Bag1 did not disturb the primary function of Akt or Raf, as phosphorylation of the forkhead transcription factor FKHR and activation of extracellular signal-regulated kinase (Erk)-1/2 were not affected. However, the defect was associated with the disturbance of a tripartite complex formed by Akt, B-Raf and Bag1, in addition to the absence of Bad phosphorylation at Ser136. We also observed reduced expression of members of the inhibitor of apoptosis (IAP) family. Our data show that Bag1 is a physiological mediator of extracellular survival signals linked to the cellular mechanisms that prevent apoptosis in hematopoietic and neuronal progenitor cells.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaline Phosphatase / metabolism
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Analysis of Variance
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Animals
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Blotting, Southern / methods
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Blotting, Western / methods
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Carrier Proteins / metabolism
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Cell Count / methods
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Cell Differentiation / physiology*
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Cell Survival / physiology
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Cells, Cultured
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DNA-Binding Proteins
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Electron Transport Complex IV / metabolism
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Embryo, Mammalian
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Eye Proteins / metabolism
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Fibroblasts / metabolism
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HSP70 Heat-Shock Proteins / deficiency
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Hematopoietic Stem Cells / physiology*
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Homeodomain Proteins / metabolism
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Immunohistochemistry / methods
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Immunoprecipitation / methods
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In Situ Nick-End Labeling / methods
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Intermediate Filament Proteins / metabolism
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Isoenzymes / metabolism
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Liver / cytology
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Liver / growth & development
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Liver / metabolism
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Membrane Proteins / deficiency
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Membrane Proteins / physiology*
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Mice
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Mice, Knockout
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Motor Neurons / physiology*
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Mutation
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Nerve Tissue Proteins / metabolism
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Nestin
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Neurofilament Proteins / metabolism
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PAX6 Transcription Factor
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Paired Box Transcription Factors
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Propidium
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins B-raf / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / biosynthesis
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RNA, Small Interfering / metabolism
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Rats
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Spinal Cord / cytology*
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Spinal Cord / growth & development
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Spinal Cord / metabolism
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Transcription Factors
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Transfection / methods
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bcl-Associated Death Protein
Substances
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BCL2-associated athanogene 1 protein
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Bad protein, mouse
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Bad protein, rat
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Carrier Proteins
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DNA-Binding Proteins
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Eye Proteins
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HSP70 Heat-Shock Proteins
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Homeodomain Proteins
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Intermediate Filament Proteins
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Isoenzymes
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Membrane Proteins
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Nerve Tissue Proteins
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Nes protein, mouse
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Nes protein, rat
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Nestin
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Neurofilament Proteins
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PAX6 Transcription Factor
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Paired Box Transcription Factors
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Pax6 protein, mouse
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Pax6 protein, rat
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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Transcription Factors
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bcl-Associated Death Protein
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neurofilament protein M
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Propidium
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Electron Transport Complex IV
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Akt1 protein, rat
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Braf protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-akt
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Alpi protein, rat
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Alkaline Phosphatase