Development of novel anti-inflammatory drugs on the basis of prostaglandin A1 structure

基于前列腺素A1结构的新型抗炎药物的开发

• 批准号: 13557043
• 负责人: NAKANISHI Makoto
• 金额: $ 9.02万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557043/
• 关键词: Inflammation; NF-kB; Prostaglandin; IKK; NAK; NAP1; apoptosis; TNF-α; NF-KB

The IKK-related kinase NAK contributes to the activation of NF-κB-dependent gene transcription. Here we identify NAP1 (NAK-associated protein 1), a protein that interacts with NAK and its relative IKKε. NAP1 activates NAK and facilitates its oligomerization. Interestingly, the NAK-NAP1 complex itself effectively phosphorylated serine 536 of the p65/RelA subunit of NF-κB and this activity was stimulated by tumor necrosis factor-α (TNF-α). Overexpression of NAP1 specifically enhanced cytokine-induction of an NF-κB-dependent, but not AP-1-dependent reporter. Depletion of NAP1 reduced NF-κB-dependent gene expression and sensitized cells to TNF-α-induced apoptosis. These results define NAP1 as an activator of IKK-related kinases and suggest that the NAK-NAP1 complex may protect cells from TNF-α-induced apoptosis by promoting NF-κB activation.

IKK相关激酶NAK参与激活依赖于NF-κB的基因转录。在这里，我们确定了NAK相关蛋白1(NAK相关蛋白1)，它是一种与NAK及其相关IKKε相互作用的蛋白。NAP1激活NAK，促进其寡聚化。有趣的是，NAKNAP1复合体本身有效地磷酸化了NF-κB的p65/relA亚基的丝氨酸536，并且这种活性被肿瘤坏死因子-α(Tumor Nunction Factor-α)刺激。NAP1的过表达特异性地增强了依赖于NF-κB的细胞因子的诱导，而不是依赖于AP-1的报告。NAP1的缺失降低了NF-κB依赖基因的表达，并使细胞对α诱导的细胞凋亡敏感。这些结果表明，NAP1是一种IKK相关激酶的激活剂，提示NAK-NAP1复合体可能通过促进NF-αB的激活来保护细胞免受肿瘤坏死因子-κ诱导的细胞凋亡。

项目成果

Burgers, P.M.: "Eukaryotic DNA polymerases : proposal for a revised nomenclature"J. Biol. Chem.. 274. 43487-43490 (2001)

Burgers, P.M.：“真核 DNA 聚合酶：修订命名法的提案”J.

Li, S.F.: "Genomic structure and characterization of the promoter region of the human NAK gene"Gene. 304. 57-64 (2003)

Li，S.F.：“人类 NAK 基因启动子区域的基因组结构和特征”基因。

Kobayashi, Y.: "Hydrocephalus, situs inversus, Chronic sinusitis, and male infertileity in DNA polymerase lambda-deficient mice : possible implication for the pathogenesis of immotile cilia syndrome"Mol. Cell. Biol.. 22. 2769-2776 (2002)

Kobayashi, Y.：“DNA 聚合酶 lambda 缺陷小鼠的脑积水、内脏逆位、慢性鼻窦炎和男性不育：对不动纤毛综合征发病机制的可能影响”Mol。

Buscemi, G.: "Nbs1 dependence of Chk2 activation after DNA-damage"Mol. Cell. Biol.. 21. 5214-5222 (2001)

Buscemi, G.：“DNA 损伤后 Chk2 激活的 Nbs1 依赖性”Mol。

Ding, X.: "Different hepatitis B virus genotype distributions among asymptomatic carriers and patients with liver diseases in Nanning, southern China"Hepatology Res.. 22. 37-44 (2002)

丁X.：“南宁市无症状携带者与肝病患者乙型肝炎病毒基因型的不同分布”，肝病研究. 22. 37-44 (2002)