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Traf5在体内的功能作用，我们通过基因靶向产生了TRAF5缺陷小鼠。在TRAF5^< - / - >小鼠中未废除通过TNF，CD27和CD40激活NF-KB或JNK/SAPK。在TRAF5^< - / - > T细胞中，CDZ7介导的共刺激信号也受损。总的来说，这些结果表明TRAF5参与CD40和CD27-介导的信号传导2。为了进一步研究TRAF2和TRAF5的功能，我们已经生成了TRAF2-和TRAF5双缺陷小鼠。 TNF诱导的NF-KB核转运在鼠类胚胎成纤维细胞（MEF）中严重受损，这些鼠（MEFS）源自TRAF2^< - /-> traf5^< - / - >（dko）小鼠，而IL-1诱导的NF-KB核易位并不损害。仅在TNF存在下，小鼠大大减少了。总的来说，这些结果表明TRAF2和TRAF5都与TNF诱导的NF-KB激活有关，并且也传输了抗凋亡信号3。为了研究DKO MEF对TNF诱导的细胞死亡的敏感性提高的分子机制，我们检查了各种与凋亡相关基因的表达水平。在研究的各种基因中，与野生型的MEF相比，DKO MEF在DKO MEF中诱导A1/BF1-1是抗凋亡BC1-2家族的成员。但是，将A1/BF1-1稳定转染到DKO MEF中仅部分抑制了TNF诱导的细胞死亡。除A1/BF1-1以外的其他分子可能与TNF诱导的细胞死亡有关。

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