Abstract
The leukemogenic tyrosine kinase fusion protein Bcr-Abl activates a Ras-dependent pathway required for transformation. To examine subsequent signal transduction events we measured the effect of Bcr-Abl on two mitogen-activated protein kinase (MAPK) cascades--the extracellular signal-regulated kinase (ERK) pathway and the Jun N-terminal kinase (JNK) pathway. We find that Bcr-Abl primarily activates JNK in fibroblasts and hematopoietic cells. Bcr-Abl enhances JNK function as measured by transcription from Jun responsive promoters and requires Ras, MEK kinase (MAPK/ERK kinase kinase), and JNK to do so. Dominant-negative mutants of c-Jun, which inhibit the endpoint of the JNK pathway, impair Bcr-Abl transforming activity. These findings implicate the JNK pathway in transformation by a human leukemia oncogene.
Publication types
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Comparative Study
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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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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Transformation, Neoplastic*
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Cells, Cultured
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Enzyme Activation
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Fibroblasts
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Fusion Proteins, bcr-abl / metabolism*
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Hematopoietic Stem Cells
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Humans
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JNK Mitogen-Activated Protein Kinases
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
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MAP Kinase Kinase Kinase 1*
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Mitogen-Activated Protein Kinases*
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Mutation
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Oncogenes*
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-jun / metabolism*
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Signal Transduction
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Transcription, Genetic
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ras Proteins / metabolism
Substances
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Proto-Oncogene Proteins c-jun
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Fusion Proteins, bcr-abl
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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ras Proteins