Molecular mechanism of signal transduction mediated by Rel/NFkB

Rel/NFkB介导的信号转导分子机制

• 批准号: 05454642
• 负责人: INOUE Jun-ichiro
• 金额: $ 3.71万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454642/
• 关键词: Transcription factor; Rel; NFkappaB; Signal transduction; Molecular biology; NFkB; 蛋白質間相互作用

1. Molecular Mechanism of Rel/NFkappaB activationActivation of Rel/NFkappaB is achieved by the signal-induced rapid phosphorylation and degradation of inhibitory protein IkappaBalpha. To explore the molecular mechanism of signal-induced depletion of IkappaBalpha, we have delineated the domain in IkappaBalpha that is required for the regulation. In contrast to the previous reports, the PEST-like sequences dispensable for TNFalpha-induced degradation whereas the six ankyrin repeats are required. However, neither ankyrin repeats nor carboxyl-terminal region including the PEST-like sequences are required for TNFalpha-induced phosphorylation.2. Signal transduction pathway emanating from membrane receptors to Rel/IkappaBalpha complexWe have found that signals emanating from CD40 link to Rel/NFkappaB activation. To identify molecules which transduce CD40 signalings, we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the cytoplasmic tail of CD40, cDNAs encoding a putative signal transducer protein, designated TRAF5 and TRAF6, have been molecularly cloned. Overexpression of TRAF5 or TRAF6 activates transcription factor NFkappaB.Thus, we are looking for the down stream transducer of these proteins. Furthermore we have demonstrated that cupric ion blocks NFkappaB activation through inhibiting the signal-induced phosphorylation of IkappaBalpha Target molecule of cupric ion remain to be identified.3. Identification of novel kappaB proteinsTo identify novel IkappaB cDNAs, an expression cDNA library has been screened using p65 subunit of NFkappaB as a probe. This study is still in the progress.4. Chromosomal assignment of rel, NFkappaB and IkappaB genes in RatWe have indentified that NFKB-1 (p50, IkappaBgamma) in on the Rat chromosome #2. Assignment of rel and IkappaBalpha is still in the Progress.

1。rel/nfkappab rel/nfkappab激活活化的分子机制是通过信号诱导的快速磷酸化和抑制蛋白ikappabalpha降解来实现的。为了探索信号诱导的ikappabalpha耗竭的分子机制，我们已经描绘了调节所需的Ikappabalpha中的域。与先前的报道相反，需要tnfalpha诱导的降解的害虫样序列，而需要六个脚踝蛋白重复序列​​。但是，TNFALPHA诱导的磷酸化不需要Ankyrin重复或羧基末端区域，包括害虫样序列。2。从膜受体到REL/IKAPPABALPHA COMFFELKS发出的信号转导途径我们发现，从CD40链接到REL/NFKAPPAB激活发出的信号。为了鉴定传递CD40信号的分子，我们将酵母的两杂交系统用于编码蛋白质的克隆cDNA，该蛋白质结合了CD40的细胞质尾巴的蛋白质，编码了指定的TRAF5和TRAF6的推定信号传感器蛋白的cDNA，已指定为TRAF5和TRAF6。 TRAF5或TRAF6的过表达激活转录因子NFKAPPAB。因此，我们正在寻找这些蛋白质的下流透射剂。此外，我们已经证明，铜离子可以通过抑制信号诱导的库巴巴巴靶标分子的信号诱导的磷酸化来阻断NFKAPPAB激活。3。鉴定新型Kappab蛋白质鉴定的新型Ikappab cDNA，已经使用NFKappab的p65亚基作为探针筛选了表达cDNA库。这项研究仍在进展中。4。 RERWWE中RER，NFKAPPAB和IKAPPAB基因的染色体分配肯定是大鼠染色体＃2中的NFKB-1（P50，Ikappabgamma）。 Rel和Ikappabalpha的分配仍在进步中。

项目成果

Ishida, T., Kobayashi, N., Tojo, T., Ishida, S., Yamamoto, T.and Inoue, J.: "CD40 signaling-mediated induction of Bcl-xL,Cdk4 and Cdk6 : Implication of their co-operation in selective B cell growth" J.Immunol.155. 5527-5535 (1995)

Ishida, T.、Kobayashi, N.、Tojo, T.、Ishida, S.、Yamamoto, T. 和 Inoue, J.：“CD40 信号介导的 Bcl-xL、Cdk4 和 Cdk6 诱导：它们的共同作用的含义

Suzuki,K.: "Molecular cloning of cDNA encoding the Xenopus homologue of mammalian RelB." Nuc.Acids Res. 23. 4664-4669 (1995)

Suzuki,K.：“编码哺乳动物 RelB 爪蟾同源物的 cDNA 的分子克隆。”

Ishida,T.: "CD40signaling-mediated induction of Bcl-xL,Cdk4 and Cdk6 : Implication of their co-operation in selective B cell growth." J.Immunol.155. 5527-5535 (1995)

Ishida,T.：“CD40 信号介导的 Bcl-xL、Cdk4 和 Cdk6 诱导：它们在选择性 B 细胞生长中合作的意义。”

Otuka, M., Fujita, M., Aoki, T., Sugiura, Y., Ishii, S., Yamamoto, T., and Inoue, J.: "Novel zinc chelators which inhibit the binding of HIV-EP1 (HIV enhancer binding protein) to NFkappaB recognition sequence" J.Med.Chem. 37. 4267-4269 (1994)

Otuka, M.、Fujita, M.、Aoki, T.、Sugiura, Y.、Ishii, S.、Yamamoto, T. 和 Inoue, J.：“抑制 HIV-EP1（HIV-EP1）结合的新型锌螯合剂

Hirai,H.: "Tax protein of human T cell leukemia virus type 1(HTL V-1)binds to the ankyrin motifs of IkB and induces nuclear translocation of NFkB proteins for transcriptional activation" Proc.Natl.Acad.Sci.USA. 91. 3584-3588 (1994)

Hirai,H.：“人 T 细胞白血病病毒 1 型 (HTL V-1) 的 Tax 蛋白与 IkB 的锚蛋白基序结合，并诱导 NFkB 蛋白的核转位以实现转录激活”Proc.Natl.Acad.Sci.USA。