p56(dok-2) as a cytokine-inducible inhibitor of cell proliferation and signal transduction.
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.
Suzu
S
S
Biochemical Research Laboratory, Morinaga Milk Industry Co. Ltd, Higashihara, Zama-city, Kanagawa 228-8583, Japan.
Tanaka-Douzono
M
M
Nomaguchi
K
K
Yamada
M
M
Hayasawa
H
H
Kimura
F
F
Motoyoshi
K
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016375:Antisense Elements (Genetics); D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015151:Immunoblotting; D007377:Interleukin-3 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D016375:Antisense Elements (Genetics); D002352:Carrier Proteins; D016207:Cytokines; C498444:Dok2 protein, mouse; D007377:Interleukin-3; D010750:Phosphoproteins; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor