Abstract
Growth arrest and DNA damage-inducible protein 45alpha (GADD45alpha) is an important cell cycle checkpoint protein that arrests cells at G2/M phase by inhibiting the activity of G2-specific kinase, cyclin B/p34cdc2. We report here that arsenite induces GADD45alpha expression in a p53-independent fashion and that this GADD45alpha induction by arsenite is regulated by NF-kappaB and c-Jun-N-terminal kinase (JNK) oppositely. In human bronchial epithelial cells overexpressing a kinase-mutated form of IkappaB kinase beta (IKKbeta-KM), the activation of NF-kappaB was inhibited. However, the G2/M cell cycle arrest and expression of GADD45alpha was substantially enhanced in response to arsenite in these cells. Expression of a dominant-negative mutant of SEK1 that blocks JNK activation decreased arsenite-induced GADD45alpha expression. Analysis of GADD45alpha expression in both wild-type and p53-/- fibroblasts indicated that the induction of GADD45alpha by arsenite was independent of the status of p53 protein.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arsenites / pharmacology*
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Bronchi / cytology
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Bronchi / physiology
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Cell Cycle / physiology*
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Cell Line
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DNA Damage*
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Enzyme Activation
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Fibroblasts / physiology
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G2 Phase
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GADD45 Proteins
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Gene Expression Regulation / drug effects*
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Genes, p53
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Humans
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I-kappa B Kinase
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Intracellular Signaling Peptides and Proteins
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JNK Mitogen-Activated Protein Kinases
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Kinetics
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MAP Kinase Kinase 4*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism*
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Mitosis
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics*
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Recombinant Proteins / metabolism
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Respiratory Mucosa / cytology
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Respiratory Mucosa / physiology*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Arsenites
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Proteins
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Recombinant Proteins
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Tumor Suppressor Protein p53
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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MAP2K4 protein, human
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Mitogen-Activated Protein Kinase Kinases
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arsenite