Abstract
The cytoplasmic tyrosine kinase Abl is a Src substrate required for platelet-derived growth factor (PDGF) receptor signaling leading to Myc expression and DNA synthesis. Abl targets are, however, ill defined. Here we report that the small GTPase Rac is an important effector of its mitogenic function. PDGF-induced Rac activation was impaired in cells with inactive Abl and active Rac overcame the mitogenic defects found in these cells. Rac function required both a Jun N-terminal kinase (JNK) and a NADPH oxidase (Nox) pathway. Furthermore, co-activation of JNK and Nox were sufficient to mimic the Rac mitogenic rescue. Abl also regulated PDGF-induced JNK and Nox activation. Finally, we found that Myc is an important target of this signaling cascade: Myc induction was sensitive to small inhibitors of JNK and Nox activities and forced expression of Myc overcame the G1 block induced by dominant interfering mutants of mitogen-activated protein kinase kinase 4 (MKK4) and Nox2 activating subunit. We concluded that cytoplasmic Abl operates on a Rac/JNK and a Rac/Nox pathway for PDGF-induced Myc induction and DNA synthesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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DNA / biosynthesis
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DNA Replication / drug effects
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DNA Replication / genetics*
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Enzyme Induction / genetics
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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G1 Phase / drug effects
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G1 Phase / genetics
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Genes, cdc / drug effects
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Mice
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Mitosis / drug effects
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Mitosis / genetics*
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Mutation / physiology
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NADH, NADPH Oxidoreductases / genetics
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NADH, NADPH Oxidoreductases / metabolism
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NADPH Oxidase 1
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NIH 3T3 Cells
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Platelet-Derived Growth Factor / pharmacology
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Platelet-Derived Growth Factor / physiology*
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Receptors, Platelet-Derived Growth Factor / genetics
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Receptors, Platelet-Derived Growth Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Up-Regulation / genetics
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rac GTP-Binding Proteins / genetics
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rac GTP-Binding Proteins / metabolism*
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-myc
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DNA
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NADH, NADPH Oxidoreductases
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NADPH Oxidase 1
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Receptors, Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-abl
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src-Family Kinases
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Map2k4 protein, mouse
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rac GTP-Binding Proteins