Abstract
Wee1 kinase downregulates the M-phase promoting factor, a complex of cdc2 and cyclin B kinase, that controls mitotic cell division. We isolated human wee1 kinase gene promoter and found that it contained one AP-1-binding motif in its promoter region (5'-CGAGTCA-3'; -823/-817), through which wee1 kinase gene was directly transactivated by c-Fos/AP-1. In rheumatoid synovial cells, wee1 kinase was increased in conjunction with the increase of c-Fos/AP-1 and the substrate of wee1, cdc2, was phosphorylated. The amount of wee1 and c-Fos and the phosphorylation of cdc2 were decreased after treatment of the cells with an inhibitor of AP-1, curcumin. A significant proportion of cultured synovial cells of the patients with rheumatoid arthritis, but not those of osteoarthritis, shifted to a tetraploid (4C) state upon long-term culture. Thus, human wee1 kinase gene is directly transactivated by and increased in association with c-Fos/AP-1, and rheumatoid synovial cells overexpressing these genes go into aberrant mitosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Amino Acid Motifs
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Arthritis, Rheumatoid / genetics*
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Arthritis, Rheumatoid / pathology
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CDC2 Protein Kinase / drug effects
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CDC2 Protein Kinase / metabolism
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Cell Cycle Proteins*
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Cells, Cultured
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Curcumin / pharmacology
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic
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HeLa Cells
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Humans
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Middle Aged
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Mitosis / physiology
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation
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Ploidies
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Promoter Regions, Genetic
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-fos / drug effects
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism*
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Substrate Specificity
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Synovial Membrane / pathology
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Transcription Factor AP-1 / chemistry
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Transcription Factor AP-1 / drug effects
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Transcription Factor AP-1 / metabolism*
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Transcriptional Activation*
Substances
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Cell Cycle Proteins
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Enzyme Inhibitors
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Nuclear Proteins
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Proto-Oncogene Proteins c-fos
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Transcription Factor AP-1
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Protein-Tyrosine Kinases
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WEE1 protein, human
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CDC2 Protein Kinase
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Curcumin