缺氧诱导因子-1降解的调控

缺氧是引起细胞损伤的重要原因,而缺氧诱导因子-1(hypoxia-inducible factor,HIF-1)是细胞对氧浓度改变的一系列自适应反应中重要的调节因子,也在肿瘤的发生和组织缺血中起到重要的作用。林希病肿瘤因子(product of von Hippel-lindau disease,pVHL)和缺氧诱导因子抑制因子(factor inhibiting hypoxia-inducible factor-1,FIH-1)是被公认的缺氧诱导因子诱导转录的抑制因子,与HIF-1有着复杂的相互作用,并调控其降解。研究它们的相互作用将为肿瘤及缺血性疾病的治疗提供一条崭新的途径。     

缺氧诱导因子1α蛋白质水平及活性调节

缺氧诱导因子1α不仅对于机体在缺氧条件下维持正常的生理功能具有特别重要的意义。还在肿瘤的生长以及神经细胞凋亡等病理过程中起关键作用。缺氧诱导因子1α能调节许多下游基因的表达水平,但人们对其自身的蛋白质水平和转录活性调节机制尚知之不多。最新的研究发现缺氧诱导因子1α的蛋白质水平和转录活化调节机制涉及多个信号通路。在缺氧诱导因子1α的蛋白质水平和转录活调节机制中,羟基化调节和蛋白磷酸化调节起主导作用。     

缺氧诱导因子-1α在肝癌组织中的动态表达特征及意义

目的:研究肝细胞癌(Hepatocellular carcinoma,HCC)组织中缺氧诱导因子-1α(HIF-1α)的动态表达特征及其临床价值。方法:采用WB、IHC以及PCR方法测定并比较HIF-1α在不同肝脏组织中的阳性情况以及表达量,分析HIF-1α强阳性和临床病理的关系。结果:正常肝组HIF-1α阴性率明显高于其他各组;HCC坏死组HIF-1α强阳性率最高。正常肝组HIF-1α表达量明显低于其他各组;HCC坏死组表达量最高且明显高于HCC组。中低度分化组HIF-1α强阳性较高度分化组高得多;有转移组HIF-1α强阳性较无转移组高得多。差异均具有统计学意义(P0.05)。结论:HIF-1α在肝硬化以及HCC组织中表达量均高于正常肝组织。HIF-1α表达与肿瘤分化的程度以及HCC转移相关,但与有无癌栓及HBsAg表达及预后不相关,为临床治疗肝癌提供了新思路。     

缺氧诱导因子-1结构及功能的研究进展

缺氧诱导因子(hypoxia inducible factor-1,HIF-1)是一种介导机体对缺氧环境产生应答的转录因子。在炎症及实体肿瘤周围的组织大多存在缺氧现象。在缺氧条件下,HIF-1α和HIF-1β两个亚基结合,形成HIF-1并迅速活化,参与机体缺氧环境的适应,并在胚胎发育、多种肿瘤及心肺疾病等发生发展中起到重要作用。因此,更好地认识HIF-1的功能及意义,对进一步地认识与其相关生命过程和疾病本质以及研发新的治疗手段具有重要意义。     

缺氧诱导因子1

缺氧诱导因子1是缺氧诱导细胞所产生的一种蛋白质,由一个120 ku的α亚基和一个91～94 ku的β亚基组成的异源二聚体.在缺氧条件下,促进红细胞生成素和糖酵解酶等基因的转录和表达,维持机体氧稳态.     

低氧诱导因子 -1α 作为肝癌治疗靶点的研究进展

低氧在实体瘤中常有发生,实体瘤的低氧能刺激低氧诱导因子（HIF-1α）的过度表达。HIF-1α 的高表达能够进一步促进癌细胞的增殖、浸润能力,甚至能够降低癌细胞对放化疗的敏感性。以 HIF-1α 为靶点的肝癌药物治疗方案已经越来越受到临床及相关研究者的关注,抑制 HIF-1α 的表达可抑制肝癌转移、克服多药耐药、诱导肝癌细胞增殖和凋亡,因此通过直接或间接的手段靶向 HIF-1α 将成为治疗肝癌的有效手段。     

转录因子Rex-1：结构、表达谱和干性（stemness）调控功能

Rex-1（reduced expression1）又称Zfp-42（zinc finger protein 42）,是一种酸性锌指结构蛋白,在胚胎干细胞和部分成体干细胞中高表达,并随维甲酸（retinoid acid,RA）诱导干细胞分化而迅速下调。该分子的结构特点提示其具有转录调控的功能,对决定干细胞的状态和发育阶段发挥重要作用。     

缺氧诱导因子1和红细胞生成素3‘—增强子调节内皮细胞？…

目的和方法：将红细胞生成素（ＥＰＯ）３＇－增强子野生片断及点突变片断借脂质体主人脐静脉内皮细胞株ＥＣＶ－３０４,用半定量ＲＴ－ＰＣＲ测定正常秘缺氧诱导因子－１（ＨＩＦ－１）诱导剂氧化钴（ＣｏＣｌ２）作用下培养６ｈ的细胞环氧合酶２（ＣＯＸ－２）和血栓素合酶（ＴＸＳ）的ｍＲＮＡ。结果：ＨＩＦ－１诱导剂ＣｏＣｌ２可放ＣＯＸ－２和ＴＸＳ基因转明显增强２,向细胞导入野生ＥＰＯ３＇增强子片断可阻断ＣｏＣｌ２诱     

缺氧诱导因子-1在病毒感染中的作用

缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是一种由β亚单位和α亚单位组成的异二聚体转录因子,其表达产物参与细胞的许多生理过程。越来越多的研究提示HIF-1在病毒感染中发挥着重要作用。通过检索相关文献,对人病毒感染中HIF-1活性改变及其在病毒感染中的作用进行了综述,为研究HIF-1在病毒感染中的作用提供参考。     

缺氧诱导因子-1α表达在胃癌中的研究进展

胃癌是人类最常见的恶性肿瘤之一,严重威胁着人类的健康。大量研究表明,缺氧能促进恶性肿瘤的发展,增强其侵袭性,而缺氧诱导因子-1α(HIF-1α)是这一过程的主要调节因子,是缺氧条件下广泛存在于哺乳动物及人体内的一种转录因子,通过增加多种转录因子和靶基因产物的表达,使肿瘤在缺氧的环境下生长、增殖、侵袭及转移。本文就HIF-1α在胃癌领域的研究进展做一综述。     

A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway

Hypoxia-inducible factor (HIF)-1 is a therapeutic target in solid tumors. We report the novel benzimidazole analogue AC1-004, obtained from a chemical library using an HRE-dependent cell-based assay in colorectal carcinoma HCT-116 cells. The accumulation of hypoxia-induced HIF-1α was inhibited by compound AC1-004 in various cancer cells, including HCT-116, MDA-MB435, SK-HEP1, and Caki-1. Further, AC1-004 down-regulated VEGF and EPO, target genes of HIF-1, and inhibited in vitro tube formation of HUVEC, suggesting its potential inhibitory activity on angiogenesis. Importantly, AC1-004 was found to regulate the stability of HIF-1α through the Hsp90-Akt pathway, leading to the degradation of HIF-1α. An in vivo antitumor study demonstrated that AC1-004 reduced tumor size significantly (i.e., by 58.6%), without severe side effects. These results suggest the benzimidazole analogue AC1-004 is a novel HIF inhibitor that targets HIF-1α via the Hsp90-Akt pathway, and that it can be used as a new lead in developing anticancer drugs.     

Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.     

BRCA1和BRCA2与DNA损伤修复及转录调控

乳腺癌和卵巢癌敏感基因BRCA1和BRCA2与同源重组,DNA损伤修复,胚胎生长,转录调控及遍在蛋白化有关,其中,BRCA1和BRCA2在DNA损伤修复和转录调控中功能的确定,将有助于探讨和阐明两者的肿瘤抑制功能及其机理,作者将综述近年来有关BRCA1和BRCA2在DNA损伤修复和转录调控中功能研究的最新进展。     

The zinc chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine, increases the level of nonfunctional HIF-1alpha protein in normoxic cells

The hypoxia-inducible factor-1alpha (HIF-1alpha) subunit is activated in response to lack of oxygen. HIF-1alpha-specific prolyl hydroxylase and factor inhibiting HIF-1alpha (FIH-1) catalyze hydroxylation of the proline and asparagine residues of HIF-1alpha, respectively. The hydroxyproline then interacts with ubiquitin E3 ligase, the von Hippel-Lindau protein, leading to degradation of HIF-1alpha by ubiquitin-dependent proteasomes, while the hydroxylation of the asparagine residue prevents recruitment of the coactivator, cAMP-response element-binding protein (CBP), thereby decreasing the transactivation ability of HIF-1alpha. We found that the Zn-specific chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), enhances the activity of HIF-1alpha-proline hydroxylase 2 but the level of HIF-1alpha protein does not fall because TPEN also inhibits ubiquitination. Since the Zn chelator does not prevent FIH-1 from hydroxylating the asparagine residue of HIF-1alpha, its presence leads to the accumulation of HIF-1alpha that is both prolyl and asparaginyl hydroxylated and is therefore nonfunctional. In hypoxic cells, TPEN also prevents HIF-1alpha from interacting with CBP, so reducing expression of HIF-1alpha target genes. As a result, Zn chelation causes the accumulation of nonfunctional HIF-1alpha protein in both normoxia and hypoxia.