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IκB激酶的研究进展陈红清(中国医学科学院、中国协和医科大学皮肤病研究所,南京210042关键词IκB激酶信号转导转录因子中κ基因结合核因子(NF-κB)由属于癌基因rel表达的Rel蛋白家族的2个亚基组成,最常见的形式是由p65(Rel-A)和p5... 相似文献
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IκB家族是一组能够与转录因子NF-κB直接结合并调节NF-κB活力的蛋白.IκB蛋白结构上的普遍特点是拥有负责与NF-κB结合的多个锚蛋白(ankyrin)重复序列.IκBL包含ankyrin的重复序列并且能够抑制LPS诱导的NF-κB激活.然而,IκBL与NF-κB能否直接结合仍不确定.本文综述了IκB家族成员结构和功能上的特点,并分析了IκBL是否应被视为IκB家族成员之一. 相似文献
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Katsuhiro Zen Aly Karsan Thomas Eunson Esther Yee John M. Harlan 《Experimental cell research》1998,243(2):425
We studied the signal transduction pathways involved in NF-κB activation and the induction of the cytoprotective A20 gene by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVEC). LPS induced human A20 mRNA expression with a maximum level 2 h after stimulation. The proteasome inhibitorN-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN) and the tyrosine kinase inhibitor herbimycin A (HMA) blocked A20 mRNA expression and partially inhibited NF-κB DNA-binding activity induced by LPS treatment. LPS induced IκBα degradation at 30–60 min after treatment, but did not induce IκBβ degradation up to 120 min. In contrast, TNF-α rapidly induced IκBα degradation within 5 min and IκBβ degradation within 15 min. Cycloheximide did not prevent LPS-induced IκBα degradation, indicating that newly synthesized proteins induced by LPS were not involved in LPS-stimulated IκBα degradation. LPS-induced IκBα degradation was inhibited by ALLN, confirming that ALLN inhibits NF-κB activation by preventing IκBα degradation. Of note, HMA also inhibited LPS-induced IκBα degradation. However, tyrosine phosphorylation of IκBα itself was not elicited by LPS stimulation, suggesting that tyrosine phosphorylation of a protein(s) upstream of IκBα is required for subsequent degradation. We conclude that in HUVEC, LPS induces NF-κB-dependent genes through degradation of IκBα, not IκBβ, and propose that this degradation is induced in part by HMA-sensitive kinase(s) upstream of IκBα. 相似文献
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The IκB kinase (IKK) complex is the signal integration hub for NF-κB activation. Composed of two serine-threonine kinases (IKKα and IKKβ) and the regulatory subunit NEMO (also known as IKKγ), the IKK complex integrates signals from all NF-κB activating stimuli to catalyze the phosphorylation of various IκB and NF-κB proteins, as well as of other substrates. Since the discovery of the IKK complex components about 15 years ago, tremendous progress has been made in the understanding of the IKK architecture and its integration into signaling networks. In addition to the control of NF-κB, IKK subunits mediate the crosstalk with other pathways, thereby extending the complexity of their biological function. This review summarizes recent advances in IKK biology and focuses on emerging aspects of IKK structure, regulation and function. 相似文献
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IκB kinase (IKK) complex, the master kinase for NF-κB activation, contains two kinase subunits, IKKα and IKKβ. In addition to mediating NF-κB signaling by phosphorylating IκB proteins during inflammatory and immune responses, the activation of the IKK complex also responds to various stimuli to regulate diverse functions independently of NF-κB. Although these two kinases share structural and biochemical similarities, different sub-cellular localization and phosphorylation targets between IKKα and IKKβ account for their distinct physiological and pathological roles. While IKKβ is predominantly cytoplasmic, IKKα has been found to shuttle between the cytoplasm and the nucleus. The nuclear-specific roles of IKKα have brought increasing complexity to its biological function. This review highlights major advances in the studies of the nuclear functions of IKKα and the mechanisms of IKKα nuclear translocation. Understanding the nuclear activity is essential for targeting IKKα for therapeutics. 相似文献
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NF-κB(nuclear factor-κB)是一种广泛存在的核转录因子,它参 与多种基因的转录调控,与许多重要的生理病理过程关系密切。许多细胞外刺激可诱导NF- κB的活性,位点特异的NF-κB抑制蛋白(IκB)的磷酸化对于激活NF-κB有重要意义。I κK(IκB kinase)的发现为进一步了解NF-κB的功能和调控提供了线索。本文综述了Iκ K的结构、功能及相关信号转导研究进展。 相似文献
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NFκB是细胞活化和产生细胞因子的重要转录调控因子。在静止细胞胞液中,NFκB与IκB(κB的抑制剂)结合,处于失活状态。细胞活化传递的信号激活IκB激酶(IKK),IKK催化IκBα(Ser32、Ser36)和IκBβ(Ser19、Ser32)磷酸化,使IκB与NFκB解离后被降解,于是NFκB进入核内,调节多种基因转录[1]。1.IKK的结构及其与功能的关系IKK复合物的分子量约600~900kD,主要由3个亚单位组成:IKKα、IKKβ和IKKγ[2]。其中IKKα和IKKβ组成功能性异二聚体并以二聚体表现活性,在一定条件下(如… 相似文献
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殷莉群 《国外医学:分子生物学分册》2000,22(4):223-227
真核细胞枋转导因子Rel/NF-κB家族广泛调控着自昆虫至人类的免疫和炎症反应中一系列基因的表达。静息状态下,NF-κB二聚体与抑制性蛋白IκB结合而存在于胞质中,当细胞受外源性刺激哩,NF-κB活化进入核内发挥其功能。目前,外源性信号活化NF-κB的机制已初步阐明,Rel/NF-κB/IκB/IKK信号转导途径在蛋白质水平的相互调控,以及在肿瘤发生中的意义的研究也已获得一定进展。本文综述了近年来 相似文献
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IκB激酶的激活及其在NF-κB活化过程中的作用 总被引:3,自引:0,他引:3
在NF-κB二聚体活化过程中,IκB激酶(IKK)通过对抑制性蛋白κB(IκBs)的磷酸化而扮演关键的角色.IKK复合物在胞浆内有多种存在形式,其中,IKK-α、IKK-β两者氨基酸序列52%的同源性,空间构象相似,常为催化亚单位,而IKK-γ则为调节亚单位,它们以不同的方式活化IκBs.核因子κB诱导激酶(NIK)与丝裂原活化蛋白激酶激酶激酶-1(MEKK1)均为IKK的上游激酶,NIK可引起IKK-α Ser176、IKK-β相应位点的磷酸化,而MEKK1主要引起IKK-β的活化.通过级联反应,使IκBs磷酸化而与NF-κB解离,致使NF-κB被激活并易位入核,启动免疫及炎症相关的基因转录. 相似文献
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Yue-Ping Liu Jin-Kun Wen Yi-Bing Wu Jia Zhang Bin Zheng Di-Qun Zhang Mei Han 《Phytomedicine》2009,16(2-3):156-160
To determine the chemical constituents responsible for pharmacological effects of Inula britannica-F., three specific sesquiterpene lactones in Inula britannica were isolated from chloroform extract and identified, including britannilactone (BL), 1-O-acetylbritannilactone (ABLO), and 1,6-O,O-diacetylbritannilactone (ABLOO). Electrophoretic mobility shift assay (EMSA) was performed to detect the nuclear translocation of nuclear factor-κB (NF-κB) p65. The expressions of IκBα, pIκBα, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IκB kinase α/β (IKKα/β) and NF-κB kinase (NIK) were detected by Western blot and RT-PCR. We found that acetyl side groups enhanced the inhibitory action of the agents on LPS/IFN-γ-induced iNOS and COX-2 expression. Their inhibiting activity was positive correlation with the acetyl side group number. The effects of LPS/IFN-γ were reversed by ABLOO, and BL without acetyl side groups showed only a weak inhibitory action. Further study indicated that ABLOO markedly inhibited the phosphorylation of IKKβ down to based level, but not IKKα, corresponding with decreased in IκBα degradation and phosphorylation induced by LPS/IFN-γ, resulting in the suppression of NF-κB nuclear translocation and activity. These results suggest that the acetyl moieties add to the lipophilicity, and consequently enhance cellular penetration, so that ABLOO possess the most anti-inflammatory effect and may be a potent lead structure for the development of therapeutic and cytokine-suppressing remedies valuable for the treatment of various inflammatory diseases. 相似文献
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Activation of NF-κB by alloferon through down-regulation of antioxidant proteins and IκBα 总被引:1,自引:0,他引:1
Ryu MJ Anikin V Hong SH Jeon H Yu YG Yu MH Chernysh S Lee C 《Molecular and cellular biochemistry》2008,313(1-2):91-102
Alloferon is a 13-amino acid peptide isolated from the bacteria-challenged larvae of the blow fly Calliphora vicina. The pharmaceutical value of the peptide has been well demonstrated by its capacity to stimulate NK cytotoxic activity and interferon (IFN) synthesis in animal and human models, as well as to enhance antiviral and antitumor activities in mice. Antiviral and the immunomodulatory effectiveness of alloferon have also been supported clinically proved in patients suffering with herpes simplex virus (HSV) and human papilloma virus (HPV) infections. To elucidate molecular response to alloferon treatment, we initially screened a model cell line in which alloferon enhanced IFN synthesis upon viral infection. Among the cell lines tested, Namalva was chosen for further proteomic analysis. Fluorescence difference gel electrophoresis (DIGE) revealed that the levels of a series of antioxidant proteins decreased after alloferon treatment, while at least three glycolytic enzymes and four heat-shock proteins were increased in their expression levels. Based on the result of our proteomic analysis, we speculated that alloferon may activate the NF-kappaB signaling pathway. IkappaB kinase (IKK) assay, Western blot analysis on IkappaBalpha and its phosphorylated form at Ser 32, and an NF-kappaB reporter assay verified our proteomics-driven hypothesis. Thus, our results suggest that alloferon potentiates immune cells by activating the NF-kappaB signaling pathway through regulation of redox potential. Since NF-kappaB activation is involved in IFN synthesis, our results provide further clues as to how the alloferon peptide may stimulate IFN synthesis. 相似文献