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p56 dok‐2 as a cytokine‐inducible inhibitor of cell proliferation and signal transduction
Author(s) -
Suzu Shinya,
TanakaDouzono Miyuki,
Nomaguchi Kouji,
Yamada Muneo,
Hayasawa Hirotoshi,
Kimura Fumihiko,
Motoyoshi Kazuo
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.19.5114
Subject(s) - biology , junb , signal transduction , microbiology and biotechnology , cytokine , cell growth , macrophage colony stimulating factor , transcription factor , immunology , macrophage , biochemistry , gene , in vitro
p56 dok‐2 acts as a multiple docking protein downstream of receptor or non‐receptor tyrosine kinases. However, the role of p56 dok‐2 in biological functions of cells is not clear. We found that transcription of the p56 dok‐2 gene in macrophages was increased markedly in response to cytokines such as macrophage colony‐stimulating factor (M‐CSF), granulocyte/macrophage‐CSF and interleukin‐3 (IL‐3). Forced expression of p56 dok–2 inhibited M‐CSF‐, granulocyte‐CSF‐, IL‐3‐ and stem cell factor‐induced proliferation of myeloid leukemia cells, M‐NFS‐60. The p56 dok‐2 ‐overexpressing cells showed an impaired induction of c‐ myc but not of c‐ jun , junB or c‐ fos when stimulated with M‐CSF. Consistent with these results, the peritoneal cavity of the hairless ( hr/hr ) strain of mutant mice, whose cells expressed less p56 dok‐2 than wild‐type mice, contained more macrophages than that of +/hr mice. Moreover, the inhibition of endogenous p56 dok‐2 expression in macrophage‐like tumor cells, J774A.1, by stable expression of antisense p56 dok‐2 mRNA accelerated cell proliferation. The study identifies a novel role for p56 dok‐2 as a molecule that negatively regulates signal transduction and cell proliferation mediated by cytokines in a feedback loop.