GADD45β/GADD45γ 与 MEKK4 构成了一条介导 T 细胞中不依赖 STAT4 的 IFNγ 产生的遗传通路。
GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells.
作者信息
Chi Hongbo, Lu Binfeng, Takekawa Mutsuhiro, Davis Roger J, Flavell Richard A
机构信息
Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
出版信息
EMBO J. 2004 Apr 7;23(7):1576-86. doi: 10.1038/sj.emboj.7600173. Epub 2004 Mar 25.
Abstract
The stress-inducible molecules GADD45beta and GADD45gamma have been implicated in regulating IFNgamma production in CD4 T cells. However, how GADD45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with GADD45 in vitro. Here we generated MEKK4-deficient mice to define the function and regulation of this pathway. CD4 T cells from MEKK4-/- mice have reduced p38 activity and defective IFNgamma synthesis. Expression of GADD45beta or GADD45gamma promotes IFNgamma production in MEKK4+/+ T cells, but not in MEKK4-/- cells or in cells treated with a p38 inhibitor. Thus, MEKK4 mediates the action of GADD45beta and GADD45gamma on p38 activation and IFNgamma production. During Th1 differentiation, the GADD45beta/GADD45gamma/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNgamma production in a process independent of STAT4.
摘要
应激诱导分子GADD45β和GADD45γ与调节CD4 T细胞中γ干扰素（IFNγ）的产生有关。然而，GADD45蛋白的功能一直存在争议。MEKK4是一种丝裂原活化蛋白激酶激酶激酶，在体外与GADD45相互作用。在此，我们培育出MEKK4缺陷小鼠，以确定该信号通路的功能和调控机制。来自MEKK4基因敲除小鼠的CD4 T细胞，其p38活性降低，γ干扰素合成存在缺陷。GADD45β或GADD45γ的表达可促进MEKK4基因野生型T细胞中γ干扰素的产生，但在MEKK4基因敲除细胞或用p38抑制剂处理的细胞中则不然。因此，MEKK4介导GADD对p38的激活作用及γ干扰素的产生。在Th1分化过程中，GADD45β/GADD45γ/MEKK4信号通路似乎整合了由T细胞受体和IL12/STAT4转导的上游信号，从而在一个独立于STAT4的过程中增强γ干扰素的产生。
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本文引用的文献
1
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Nat Immunol. 2004 Jan;5(1):38-44. doi: 10.1038/ni1020. Epub 2003 Dec 14.
2
Nuclear factor of activated T cells c is a target of p38 mitogen-activated protein kinase in T cells.活化T细胞核因子c是T细胞中p38丝裂原活化蛋白激酶的一个靶点。
Mol Cell Biol. 2003 Sep;23(18):6442-54. doi: 10.1128/MCB.23.18.6442-6454.2003.
3
Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation.转化生长因子-β诱导的细胞凋亡是通过p38激活，由Smad依赖的GADD45b表达介导的。
J Biol Chem. 2003 Oct 31;278(44):43001-7. doi: 10.1074/jbc.M307869200. Epub 2003 Aug 21.
4
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5
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Immunity. 2003 Mar;18(3):415-28. doi: 10.1016/s1074-7613(03)00057-8.
6
7
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8
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9
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10
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