Abstract
Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Antineoplastic Agents, Hormonal / pharmacology
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Apoptosis Regulatory Proteins
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Apoptosis*
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Bcl-2-Like Protein 11
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Binding Sites
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Carrier Proteins / chemistry*
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Carrier Proteins / metabolism*
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Caspases / metabolism
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Cell Line
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Cell Survival
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Cysteine Endopeptidases / metabolism*
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Gene Expression Regulation
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Glutathione Transferase / metabolism
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Humans
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K562 Cells
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Lymphoma / metabolism
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Membrane Proteins*
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Models, Biological
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Molecular Sequence Data
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Multienzyme Complexes / metabolism*
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Phosphorylation
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Proteasome Endopeptidase Complex
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Protein Isoforms
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Proto-Oncogene Proteins c-raf / metabolism
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Proto-Oncogene Proteins*
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Serine / chemistry*
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Tamoxifen / pharmacology
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Tetradecanoylphorbol Acetate
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Time Factors
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Transfection
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents, Hormonal
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Carrier Proteins
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Membrane Proteins
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Multienzyme Complexes
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Protein Isoforms
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Proto-Oncogene Proteins
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Tamoxifen
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Serine
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Glutathione Transferase
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Caspases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Tetradecanoylphorbol Acetate