低氧、低氧诱导因子-1和白血病细胞分化

低氧诱导因子-1(HIF-1)是细胞适应低氧反应的主要转录因子,由氧敏感的HIF-1α和组成性表达的HIF-1β组成.系列研究表明,低氧是肿瘤的重要微环境.相应地,HIF-1在实体瘤的发展和转移过程中发挥重要作用.本实验室研究显示,低氧通过HIF-1的转录非依赖功能,即与造血细胞分化相关的转录因子C/EBPα和Runx1/AML1等相互作用,并增加其转录活性,诱导急性髓细胞性白血病细胞分化.本文就低氧和HIF-1在白血病细胞分化中的作用作一综述.     

铜调控低氧诱导因子1转录活性的研究进展

低氧诱导因子1(hypoxia-inducible factor 1,HIF-1)是由α亚基(HIF-1α)和β亚基(HIF1β)组成的异源二聚体转录因子,在低氧情况下调控细胞组织进行血管新生等对低氧环境的反应性活动,使细胞组织适应低氧环境,是组织中调控氧稳态的关键因子。在低氧情况下,HIF-1特异性的促进一系列血管新生相关因子的表达,这一过程需要微量元素铜的参与。铜对于这一过程中HIF-1转录复合物形成及其与DNA结合都是必须的。但是当组织长期处于缺氧/低氧的环境中时,铜从组织中流失,从而导致了HIF-1调控的这些血管新生相关因子的表达受到抑制,组织的血管新生受到抑制。因此对铜特异性调控HIF-1转录活性的深入理解能够帮助我们深入理解缺血缺氧性疾病,从而为治疗缺血缺氧性疾病提供新的思路。     

多种翻译后修饰对低氧诱导因子-1α稳定性调控的机制

低氧诱导因子-1（hypoxia-inducible factor-1, HIF-1）是组织细胞对缺氧感应和调控的一类关键转录因子,在机体中广泛表达.作为细胞低氧应答反应中的重要调节因子,HIF-1能够调节100多种涉及低氧应激下细胞适应和存活的靶基因. HIF-1是由氧依赖的α亚基和细胞内稳定表达的β亚基构成的异源二聚体.其中α亚基对氧浓度变化敏感,是HIF-1的功能性亚基,它的表达活性决定了HIF-1的生物学活性.近期研究发现,HIF-1α的一系列翻译后修饰可改变其稳定性,进而调控其转录激活活性,从而参与肿瘤、低氧性肺动脉高压以及心血管疾病等的发生与发展.本文主要就HIF-1α的一列系翻译后修饰,如羟基化、泛素化、磷酸化、乙酰化、SUMO化修饰作一综述.     

HIF-1调控低氧性肺动脉高压北大核心CSCD

低氧性肺动脉高压(hypoxia-induced pulmonary hypertension,HPH)是多种慢性病高原病发病的中心环节,严重影响疾病的病程和预后。其主要特点是低氧刺激下诱发过度的肺血管收缩反应和异常的肺血管结构重塑,导致慢性肺源性心脏病的发生。低氧诱导因子-1(hypoxia inducible factor-1,HIF-1)被认为是低氧环境下感受氧变化的重要转录调控因子,可调控多种低氧相关靶基因表达,影响肺血管重塑过程。本文就低氧下HIF-1在低氧性肺动脉高压形成中的研究进展做一综述。     

缺氧诱导因子HIF-1在抗真菌免疫中的作用

缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是细胞在低氧状态下起重要作用的核转录因子。体内真菌感染部位常形成缺氧微环境,从而激活HIF-1并在抗真菌感染免疫中起到重要作用。该文就HIF-1的结构、活性调控及相关信号通路,真菌感染与缺氧的关系,HIF-1对宿主抗真菌免疫的影响等方面进行了综述。     

缺氧诱导因子HIF-1在抗真菌免疫中的作用CSCD

缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是细胞在低氧状态下起重要作用的核转录因子。体内真菌感染部位常形成缺氧微环境,从而激活HIF-1并在抗真菌感染免疫中起到重要作用。该文就HIF-1的结构、活性调控及相关信号通路,真菌感染与缺氧的关系,HIF-1对宿主抗真菌免疫的影响等方面进行了综述。     

转录因子HIF-1α及其信号通路在疾病发生中的作用研究进展

缺氧诱导因子-1α(hypoxia inducible factor-1α,HIF-1α)是缺氧条件下广泛存在于哺乳动物和人体内的一种转录因子,是应答缺氧应激的关键因子。HIF-1α是缺氧诱导因子-1(hypoxia inducible factor-1,HIF-1)的一个亚单位,受缺氧调控并调节HIF-1的活性。在缺氧条件下,HIF-1α转移到细胞核内结合HIF-1β形成有活性的HIF-1,通过与靶基因上的缺氧反应元件结合调节多种基因的转录。HIF-1α可以与上下游多种蛋白组成不同的信号通路,介导低氧信号,调控细胞产生一系列对缺氧的代偿反应,在机体的生长发育及生理和病理过程中发挥重要作用,是生物医学研究的一个焦点。对转录因子HIF-1α及其信号通路在疾病发生中的作用进行了综述,介绍了HIF-1α在动物生长发育、炎症和肿瘤中的研究概况,并进行了展望,以便更好地应用于生物医学。     

动物抗低氧胁迫相关基因的表达调控机制

体内氧浓度的稳定是机体维持自身功能的一个必要条件。在低氧条件下,机体内部在低氧信号的刺激下形成一个强大的防御体系以保护自己的组织。在采取防御的过程中,低氧诱导因子-1 (hypoxia inducible factor-1,HIF-1)、血管内皮生长因子(vascular endothelial growth factor, VEGF)、促红细胞生成素(erythropoietin, EPO)、核因子-κB (nuclear factor-κB, NF-κB)等基因表达上调。HIF-1是一个与低氧胁迫相关的转录因子,它的激活与体内氧浓度相关。VEGF是HIF-1下游的一个靶基因,它是至今发现的一个在促血管新生方面起着最关键作用的因子。NF-κB能够抑制由低氧引起的细胞凋亡。以上这些基因在动物抗低氧胁迫方面起着重要作用,综述了低氧条件下HIF-1、VEGF、EPO、NF-κB的功能、表达特性以及调控机制。     

细胞内低氧感受器:缺氧诱导因子-1脯氨酰羟化酶研究进展

哺乳动物细胞对低氧的适应性调节是通过改变一系列基因表达来实现的。调控这些基因表达最重要的转录因子是缺氧诱导因子-1（HIF-1）,而能够直接感受氧分压、作为氧感受器的一种双加氧酶——脯氨酰羟化酶（PHD）则是调节HIF-1的关键分子。常氧状况下,HIF-1α的两个关键氨基酸残基Pro402和Pro564被PHD羟基化进而被蛋白酶水解,此时细胞内无HIF-1聚集,形成一种氧分压正常的信号状态。低氧状况下,PHD羟基化HIF-1α反应受阻,HIF-1聚集并入核诱导多种靶基因表达,启动低氧应答反应。本文就PHDs家族如何调控HIF-1α及PHD的调节剂研究进展进行综述。     

低氧诱导因子-1：细胞适应氧供应改变的关键蛋白

2019年诺贝尔生理学或医学奖授予威廉·凯林(William Kaelin Jr)、彼得·拉特克里夫爵士(Sir Peter Ratcliffe)和格雷格·赛门扎(Gregg Semenza),以表彰他们在细胞感知和适应缺氧机制上做出的重要贡献.低氧诱导因子-1 (hypoxiainducible factor-1,HIF-1)在细胞适应氧供应改变中起关键作用,可作为转录因子改变基因表达,通过提高机体携氧能力、增加血液供应、改变代谢方式等途径来适应缺氧环境.而HIF-1的功能也受到各种机制调控:泛素化-蛋白酶体途径降解和转录因子活性抑制. HIF-1与抑癌蛋白(protein von Hippel-Lindau,pVHL)、脯氨酸羟化酶(proline hydroxylase,PHD)、HIF抑制因子(factor inhibiting HIF,FIH)等构成了严密有序的调节网络.本文总结了3位诺贝尔奖获得者的研究成果,并结合最新的研究进展,系统阐述了HIF-1表达量调节机制和HIF-1介导的细胞适应缺氧环境机制.     

Correlation between the expression of divalent metal transporter 1 and the content of hypoxia-inducible factor-1 in hypoxic HepG2 cells

Transferrin and transferrin receptor are two key proteins of iron metabolism that have been identified to be hypoxia-inducible genes. Divalent metal transporter 1 (DMT1) is also a key transporter of iron under physiological conditions. In addition, in the 5' regulatory region of human DMT1 (between -412 and -570), there are two motifs (CCAAAGTGCTGGG) that are similar to hypoxia-inducible factor-1 (HIF-1) binding sites. It was therefore speculated that DMT1 might also be a hypoxia-inducible gene. We investigated the effects of hypoxia and hypoxia/re-oxygenation on the expression of DMT1 and the content of HIF-1alpha in HepG2 cells. As we expected, a very similar tendency in the responses of the expression of HIF-1alpha, DMT1+IRE (iron response element) and DMT1-IRE proteins to chemical (CoCl(2)) or physical hypoxia was observed. A highly significant correlation was found between the expression of DMT1 proteins and the contents of HIF-1 in hypoxic cells. After the cells were exposed to hypoxia and subsequent normoxia, no HIF-1alpha could be detected and a significant decrease in DMT1+IRE expression (P<0.05), but not in DMT1-IRE protein (versus the hypoxia group), was observed. The findings implied that the HIF-1 pathway might have a role in the regulation of DMT1+IRE expression during hypoxia.     

Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT)

Hypoxia occurs during the development of the placenta in the first trimester and correlates with both trophoblast differentiation and the induction of telomerase activity through hTERT expression. We sought to determine the mechanism of regulation of hTERT expression during hypoxia. We show that hypoxia-inducible factor 1alpha (HIF-1alpha) and hTERT expression in the human placenta decrease with gestational age and that these are overexpressed in preeclamptic placenta, a major complication of pregnancy. Hypoxia not only transactivates the hTERT promoter activity but also enhances endogenous hTERT expression. The hTERT promoter region between -165 and +51 contains two HIF-1 consensus motifs, and in vitro reporter assays show that these are essential for hTERT transactivation by HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT expression during hypoxia, indicating that upregulation of hTERT by hypoxia is directly mediated through HIF-1. Our results provide persuasive evidence that the regulation of hTERT promoter activity by HIF-1 represents a mechanism for trophoblast growth during hypoxia and suggests that this may be a generalized response to hypoxia in various human disorders including resistance to cancer therapeutics by upregulating telomerase.