Human wee1 kinase is directly transactivated by and increased in association with c-Fos/AP-1: rheumatoid synovial cells overexpressing these genes go into aberrant mitosis.
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.
Kawasaki
Hiroki
H
Department of Rheumatology, Kobe University FHS School of Medicine, Kobe 654-0142, Japan.
Komai
Koichiro
K
Nakamura
Mikiko
M
Yamamoto
Eri
E
Ouyang
Zhufeng
Z
Nakashima
Toshie
T
Morisawa
Tae
T
Hashiramoto
Akira
A
Shiozawa
Kazuko
K
Ishikawa
Hitoshi
H
Kurosaka
Masahiro
M
Shiozawa
Shunichi
S
D000368:Aged; D020816:Amino Acid Motifs; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D008875:Middle Aged; D008938:Mitosis / Q000502:physiology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011003:Ploidies; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013583:Synovial Membrane / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; D003474:Curcumin