Abstract
The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the GADD45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
Publication types
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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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Amino Acid Sequence
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Animals
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Apoptosis
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COS Cells
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Cells, Cultured
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DNA Damage / physiology*
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Enzyme Activation
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GADD45 Proteins
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Gene Expression Regulation
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins*
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MAP Kinase Kinase Kinase 4
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MAP Kinase Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Molecular Sequence Data
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Multigene Family
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Peptide Mapping
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Protein Binding
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Protein Biosynthesis
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Protein Kinases / metabolism
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Protein Kinases / physiology*
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Proteins / genetics
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Proteins / physiology*
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Sequence Alignment
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Sequence Homology, Amino Acid
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Stress, Physiological / metabolism*
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Transfection
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p38 Mitogen-Activated Protein Kinases
Substances
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GADD45G protein, human
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Intracellular Signaling Peptides and Proteins
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Proteins
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Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 4
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MAP Kinase Kinase Kinases
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MAP3K4 protein, human
Associated data
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GENBANK/AF078077
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GENBANK/AF078078