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NF—κB因其广泛参与机体的免疫及其它应激反应而受到人们的关注,其常见的形式是由p50和p65组成的异源二聚体。细胞受到外部因素刺激后,NF-κB由细胞质转移到细胞核中,并发生磷酸化和乙酰化,启动相关基因的表达。目前研究表明受NF-κB调节的基因有200多种,其激活因子不少于150种,所以对NF-κB在各种条件下的激活过程及信号传导网络的研究具有重要的意义。本文综合了当前关于NF—κB研究的最新进展,着重阐述了由TNF-α、IL-Ⅰ及LPS刺激而引起NF—κB激活的信号传导通路,并进一步阐述了其在人类某些疾病当中的生物学功能。 相似文献
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Sun SC 《Cell research》2011,21(1):71-85
The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies. 相似文献
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昆虫NF-κB信号通路由toll和imd两条通路组成,通过转录因子NF-κB作用于靶标基因κB位点,而调节抗菌活性物质的表达。大量实验表明它能够被细菌、真菌和病毒的侵染所激活,在昆虫体液免疫中发挥着主要作用。现就昆虫的NF-κB信号通路的主要信号元件等进行综述。 相似文献
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M Laforge V Rodrigues R Silvestre C Gautier R Weil O Corti J Estaquier 《Cell death and differentiation》2016,23(1):89-98
The Optic atrophy 1 protein (OPA1) is a key element in the dynamics and morphology of mitochondria. We demonstrated that the absence of IκB kinase-α, which is a key element of the nonclassical NF-κB pathway, has an impact on the mitochondrial network morphology and OPA1 expression. In contrast, the absence of NF-κB essential modulator (NEMO) or IκB kinase-β, both of which are essential for the canonical NF-κB pathway, has no impact on mitochondrial dynamics. Whereas Parkin has been reported to positively regulate the expression of OPA1 through NEMO, herein we found that PARK2 overexpression did not modify the expression of OPA1. PARK2 expression reduced the levels of Bax, and it prevented stress-induced cell death only in Bak-deficient mouse embryonic fibroblast cells. Collectively, our results point out a role of the nonclassical NF-κB pathway in the regulation of mitochondrial dynamics and OPA1 expression.Mitochondria perform multiple functions that are critical to the maintenance of cellular homeostasis. Mitochondrial dysfunctions have been linked to the development of degenerative diseases and aging. Damaged mitochondria are removed by mitophagy, a process partially regulated by the PARK2-encoded E3 ubiquitin ligase (Parkin) in a PTEN-induced putative protein kinase 1 (PINK1)-dependent manner.1, 2, 3, 4 During mitophagy, the phosphorylation of mitofusin (Mfn) 2 by PINK1 has been suggested to induce the recruitment of Parkin to the mitochondria in cardiomyocytes.5 However, previous groups have shown that that Mfn 1 and 2 are dispensable for Parkin-dependent mitophagy in fibroblasts, whereas the Parkin-dependent degradation of these proteins may impair fusion of damaged mitochondria with the healthy network.6, 7, 8 PINK1 and Parkin thus act as a quality control machinery on the outer mitochondrial membrane (OMM) to preserve mitochondrial integrity through the ubiquitination of OMM proteins.9, 10 Moreover, through its E3 ubiquitin ligase activity,11, 12 Parkin was reported to bind to the linear ubiquitin chain assembly complex (LUBAC) and to increase the ubiquitination of NF-κB essential modulator (NEMO),13 a component of the classical NF-κB signaling pathway.14 Müller–Rischart et al. also proposed that Parkin positively regulates the expression of the mitochondrial guanosine triphosphatase Optic atrophy 1 protein (OPA1) through linear ubiquitination of NEMO.13 OPA1 is a regulator of mitochondrial inner membrane fusion and cristae remodeling.15, 16, 17 A defect in OPA1 expression is associated with mitochondrial network fragmentation and enhanced sensitivity of the cells to undergo apoptosis by promoting cytochrome c release from the mitochondria.18, 19, 20 Because NEMO-deficient mouse embryonic fibroblast (MEF) cells display a normal mitochondrial network morphology, we decided to re-examine the role of Parkin in regulating OPA1 expression through the NF-κB signaling pathway. 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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目的:观察NF-κB"圈套"(κB-decoy)寡核苷酸对LPS诱导PC12细胞中NF-κB活化的抑制过程,建立κB-de-coy抑制NF-κB活化的细胞模型。方法:将培养于6孔板的PC12细胞进行分组转染,实验组:LF2000+κB-decoy(6μg/well);对照组:LF2000+错配-decoy;正常组:LF2000。转染48h后,加入LPS(200ng/ml),作用0.5~4h。分别用免疫细胞化学染色和Westernblot方法检测PC12细胞内NF-κB的表达及活化。结果:与正常组相比较,转染错配-decoy的对照组细胞,随着LPS刺激时间的延长,NF-κB的表达和活化明显增加(P0.01),2~4h达到高峰;与对照组相比较,转染κB-decoy实验组的PC12细胞,随着LPS刺激时间的延长,NF-κB的表达处于较稳定水平,在LPS刺激的各时间点中明显低于对照组(P0.01)。结论:κB-decoy可以降低生理状态下PC12细胞内NF-κB的正常表达水平,抑制病理状态下NF-κB的活化。 相似文献
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Libing Song Chuyong Lin Hui Gong Chanjuan Wang Liping Liu Jueheng Wu Sha Tao Bo Hu Shi-Yuan Cheng Mengfeng Li Jun Li 《Cell research》2013,23(2):274-289
Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression. 相似文献
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Rel/NF-κB与神经系统疾病 总被引:1,自引:0,他引:1
自从 1 986年真核细胞核转录因子Rel/NF κB被发现以来 ,对它的研究就一直方兴未艾。Rel/NF κB参与一系列病理和生理过程反应 ,如免疫反应、炎症反应等 ,在细胞的生长、分化、粘附、凋亡等过程中也具有十分重要的作用。1 .Rel/NF κB信号转导通路在静息状态时 ,Rel/NF κB与抑制蛋白IκB结合 ,抑制其核转位信号 ,使之以无活性形式存在于胞浆中 ;胞外刺激信号如活性氧介质 (ROI)、细胞因子、神经递质、病毒、UV、内质网超载等通过转导激活IKK上游激酶MEKK 1或NIK而使IKK复合物活化 ,在酪蛋白激… 相似文献
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核因子NF-κB(Nuclear factor kappa-B,NF-κB)是一种多向性的转录因子,它参与多种炎症和免疫应答相关分子基因的表达,同时也参与调控细胞的增殖和分化。它在动脉粥样硬化、关节炎、哮喘、肿瘤等疾病的发展中都起了重要的作用。炎症是多种细胞及细胞因子参与的机体防御性反应,但严重或长期的炎症则会造成机体损伤。溃疡性结肠炎(UC)是一组以慢性、周期性炎症为特征的肠道疾病,长期、反复的肠道炎症不仅影响患者生活质量,而且增加了肠道纤维化及癌变的风险,而核因子NF-κB与炎症反应关系非常密切。本文就NF-κB的作用与UC的联系作一简要综述。 相似文献
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Yang HT Papoutsopoulou S Belich M Brender C Janzen J Gantke T Handley M Ley SC 《Molecular and cellular biology》2012,32(17):3438-3451
The role of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in innate immune signaling was investigated using macrophages from Nfkb1(SSAA/SSAA) mice, in which the IKK target serines on p105 are mutated to alanines. We found that the IKK/p105 signaling pathway was essential for TPL-2 kinase activation of extracellular signal-regulated kinase (ERK) mitogen-activate protein (MAP) kinase and modulated the activation of NF-κB. The Nfkb1(SSAA) mutation prevented the agonist-induced release of TPL-2 from its inhibitor p105, which blocked activation of ERK by lipopolysaccharide (LPS), tumor necrosis factor (TNF), CpG, tripalmitoyl-Cys-Ser-Lys (Pam(3)CSK), poly(I · C), flagellin, and R848. The Nfkb1(SSAA) mutation also prevented LPS-induced processing of p105 to p50 and reduced p50 levels, in addition to decreasing the nuclear translocation of RelA and cRel. Reduced p50 in Nfkb1(SSAA/SSAA) macrophages significantly decreased LPS induction of the IκBζ-regulated Il6 and Csf2 genes. LPS upregulation of Il12a and Il12b mRNAs was also impaired although specific blockade of TPL-2 signaling increased expression of these genes at late time points. Activation of TPL-2/ERK signaling by IKK-induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-κB-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12). Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2. 相似文献
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《Cytokine & growth factor reviews》2009,20(1):7-17
Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-κB is a set of nuclear factors that bind to consensus DNA sequences called κB sites, and is essential for osteoclast formation and survival. NF-κB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-α and IL-1, which differentially regulate classical and/or alternative NF-κB pathways in osteoclastic cells. These pathways are also modulated by NF-κB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin–proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-κB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-κB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-κB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases. 相似文献