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Analysis of the mechanism of TNF receptor-mediated NF-kB activation.

TNF受体介导的NF-kB激活机制分析。

基本信息

批准号：
11670329
负责人：
NAKANO Hiroyasu
金额：
$ 2.43万
依托单位：
JUNTENDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670329/
关键词：
TRAF TNF knockout mice NF-kB JNK apoptosis Bc1-2 anti-apoptotic genes CD27 CD40 NF-kB Tax IkB kinase

项目摘要

1. To investigate the functional role of TRAF5 in vivo, we generated TRAF5-deficient mice by gene targeting. Activation of either NF-kB or JNK/SAPK by TNF, CD27, and CD40 was not abrogated in traf5^<-/-> mice.However, traf5^<-/-> B cells showed defects in proliferation and upregulation of various surface molecules, including CD23, CD54, CD80, CD86, and Fas in response to CD40 stimulation. CDZ7-mediated costimulatory signal was also impaired in traf5^<-/-> T cells. Collectively, these results demonstrated that TRAF5 is involved in CD40- and CD27- mediated signaling.2. To investigate the function of TRAF2 and TRAF5 further, we have generated TRAF2- and TRAF5-double deficient mice. TNF-induced nuclear translocation of NF-kB was severely impaired in murine embryonic fibroblasts (MEFs) derived from traf2^<-/-> traf5^<-/-> (DKO) mice, while IL-1-induced nuclear translocation of NF-kB was not impaired.Moreover, viability of MEFs from DKO mice, but not from traf2^<-/-> mice, dramatically reduced in the presence of TNF alone. Collectively, these results indicate that both TRAF2 and TRAF5 are implicated in TNF-induced NF-kB activation and also transmit anti-apoptotic signals.3. To investigate the molecular mechanism of increased sensitivity of DKO MEFs to TNF-induced cell death, we examined the expression level of various apoptosis-related genes. Among various genes investigated, induction of A1/Bf1-1, a member of the anti-apoptotic Bc1-2 family, was severely impaired in DKO MEFs compared to wild-type ones. However, stable transfection of A1/Bf1-1 into DKO MEFs only partially inhibited TNF-induced cell death. A molecule other than A1/Bf1-1 might be critically involved in protection against TNF-induced cell death.

1.为了研究TRAF 5在体内的功能作用，我们通过基因靶向产生TRAF 5缺陷小鼠。TNF、CD 27和CD 40对traf 5 ^<-/->小鼠NF-κ B或JNK/SAPK的激活没有被消除，然而，traf 5 ^<-/-> B细胞显示出增殖缺陷和多种表面分子的上调，包括对CD 40刺激的应答中的CD 23、CD 54、CD 80、CD 86和Fas。CDZ 7介导的共刺激信号在traf 5 <-/-> T细胞中也受损。总的来说，这些结果表明TRAF 5参与了CD 40和CD 27介导的信号传导.为了进一步研究TRAF 2和TRAF 5的功能，我们产生了TRAF 2和TRAF 5双缺陷小鼠。TNF诱导的NF-kB核转位在来自traf 2 ^<-/-> traf 5 ^<-/->（DKO）小鼠的鼠胚胎成纤维细胞（MEFs）中严重受损，而IL-1诱导的NF-kB核转位没有受损。总的来说，这些结果表明TRAF 2和TRAF 5都参与了TNF诱导的NF-κ B活化，并传递抗凋亡信号.为了研究DKO MEFs对TNF诱导的细胞死亡的敏感性增加的分子机制，我们检测了各种凋亡相关基因的表达水平。在研究的各种基因中，与野生型相比，DKO MEFs中抗凋亡Bc 1 -2家族成员A1/Bf 1 -1的诱导严重受损。然而，稳定转染A1/Bf 1 -1到DKO MEFs中仅部分抑制TNF诱导的细胞死亡。A1/Bf 1 -1以外的一种分子可能在保护肿瘤坏死因子诱导的细胞死亡中起关键作用。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Yamazaki, T., Y.Hamano, H.Tashiro, K.Itoh, H.Nakano, S.Miyatake, and T.Saito.: "CAST, a novel CD3ε-binding protein transducing activation signal for interleukin-2 production in T cells."J.Biol. Chem. 274. 1873-1880 (1999)

Yamazaki, T.、Y.Hamano、H.Tashiro、K.Itoh、H.Nakano、S.Miyatake 和 T.Saito.：“CAST，一种新型 CD3ε 结合蛋白转导激活信号，用于 T 中白细胞介素 2 的产生细胞。”《生物化学杂志》274. 1873-1880 (1999)

DOI：
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Sanz,L.: "The atypical PKC-interacting protein p62 channels NF-κB activation by the IL-1-TRAF6 pathway."EMBO J. 19. 1576-1586 (2000)

Sanz, L.：“非典型 PKC 相互作用蛋白 p62 通过 IL-1-TRAF6 途径激活 NF-κB。 EMBO J. 19. 1576-1586 (2000)

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Matsushima, A., T.Kaisho, P.D.Rennert, H.Nakano, K.Kurosawa, D.Uchida, K.Takeda, S.Akira, and M.Matsumoto.: "Essential role of nuclear factor NF-kB-inducing kinase and inhibitor of kB (IkB) kinase α in NF-kB activation through lymphotoxin β receptor, but

Matsushima, A.、T.Kaisho、P.D.Rennert、H.Nakano、K.Kurosawa、D.Uchida、K.Takeda、S.Akira 和 M.Matsumoto.：“核因子 NF-kB 诱导激酶的重要作用和 kB (IkB) 激酶 α 抑制剂通过淋巴毒素 β 受体激活 NF-kB，但是