p56dok-2 as a cytokine-inducible inhibitor of cell proliferation and signal transduction
p56dok-2 as a cytokine-inducible inhibitor of cell proliferation and signal transduction
复制标题
DOI：
10.1093/emboj/19.19.5114
复制
发表时间：
2000-10-02
期刊：
影响因子：
11.4
通讯作者：
Motoyoshi, K
中科院分区：
文献类型：
--
作者：
Suzu, S;Tanaka-Douzono, M;Motoyoshi, K
p56（dok-2）作为受体或非受体酪氨酸激酶下游的多对接蛋白。然而，p56（dok-2）在细胞生物学功能中的作用尚不清楚。我们发现，巨噬细胞中p56（dok-2）基因的转录在对细胞因子如巨噬细胞集落刺激因子（M-CSF）、粒细胞/巨噬细胞-CSF和白细胞介素-3（IL-3）的应答中显著增加。p56 dok-2的强制表达抑制M-CSF、粒细胞-CSF、IL-3和干细胞因子诱导的髓系白血病细胞M-NFS-60的增殖，当用M-CSF刺激时，p56（dok-2）过表达细胞显示c-myc的诱导受损，但c-jun、junB或c-fos的诱导不受损。与这些结果一致，无毛（hr/hr）突变小鼠品系的腹腔中含有比+/hr小鼠更多的巨噬细胞，所述无毛（hr/hr）突变小鼠品系的细胞表达比野生型小鼠少的p56（dok-2）。此外，通过稳定表达反义p56（dok-2）mRNA来抑制巨噬细胞样肿瘤细胞J774A.1中内源性p56（dok-2）的表达，促进细胞增殖。该研究确定了p56 dok-2作为一种负调节信号转导和细胞增殖的分子在反馈回路中由细胞因子介导的新作用。
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 p56dok-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 p56dok-2 as a molecule that negatively regulates signal transduction and cell proliferation mediated by cytokines in a feedback loop.