HIF-1 and human disease: one highly involved factor.
HIF-1 and human disease: one highly involved factor.
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DOI：
10.1101/gad.14.16.1983
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发表时间：
2000-08
影响因子：
10.5
通讯作者：
G. Semenza
中科院分区：
文献类型：
--
作者：
G. Semenza
氧稳态代表了人类发育和生理学的重要组织原则。氧化磷酸化产生ATP的基本要求与细胞脂质、核酸和蛋白质的氧化损伤风险相平衡。因此，细胞和全身O2浓度通过影响多种细胞蛋白质活性和表达的短效和长效反应途径受到严格调节（综述见Semenza 1999 a）。心脏病、癌症、脑血管疾病和慢性阻塞性肺病破坏了这种微妙的平衡，这些疾病是最常见的死亡原因，占美国所有死亡人数的三分之二（Greenlee 2000）。氧稳态对发育、生理学和疾病病理生理学的基本重要性的认识正在增长，但仍不完整。知识获取目前是指数，当一个包括领域，如血管生成在缺血性或肿瘤性疾病中的作用，其中研究人员正在研究氧稳态，即使他们可能不会解释他们的研究在这个广泛的生理背景。血管内皮生长因子（VEGF）在血管生成中起重要作用（综述参见费拉拉和Davis-Smyth 1997;费拉拉1999）。VEGF表达的调节说明了如何通过多种分子机制降低O2可用性（缺氧）引起生理反应。当大多数细胞类型经历缺氧时，VEGF表达被诱导，从而提供了一种机制，通过该机制可以根据需要优化组织灌注。在低氧细胞中，VEGF mRNA的稳态水平增加是由于产生增加（转录激活）和破坏减少（mRNA稳定化）。尽管总体蛋白质合成响应于缺氧而被抑制，但VEGF mRNA通过使用内部核糖体进入位点被有效地翻译成蛋白质（Stein等，1998）。最后，当内皮细胞暴露于缺氧时，VEGF受体FLT-1的表达也被诱导（Gerber et al.1997）。该过程的第一个基本步骤是转录激活，其通过缺氧诱导因子1（HIF-1）与位于人VEGF基因转录起始位点1 kb 5处的顺式作用缺氧反应元件的结合来介导（Forsythe等，1996）。HIF-1是由HIF-1和HIF-1亚基组成的碱性螺旋-环-螺旋PAS蛋白（Wang and Semenza 1995; Wang et al. 1995）。HIF-1表达和HIF-1转录活性受细胞内O2浓度的精确调节（综述参见Semenza 1999 b，2000 a; Wenger 2000）。O2浓度变化导致HIF-1活性变化的传感和信号转导的分子机制知之甚少，但最近的数据表明O2信号转化为氧化还原信号（Chandel et al.2000; Haddad et al.2000），其可以触发激酶级联和/或直接调节HIF-1（综述参见Semenza，1999 a，B; Chandel和Schumacker，2000）。HIF-1活性的调节发生在多个水平。尽管HIF-1 mRNA在组织培养细胞中组成型表达，但其在体内由缺氧或缺血显著诱导（Yu et al.1998; Bergeron et al.1999）。HIF-1蛋白表达在非缺氧细胞中通过泛素化和蛋白酶体降解负调控（Salceda and Caro 1997; Huang et al.1998; Kallio et al.1999）。在缺氧条件下，HIF-1蛋白水平显著增加，而泛素化的部分减少（Sutter等，2000）。HIF-1的核定位也可由缺氧诱导（Kallio等，1998）。HIF-1的羧基末端一半含有两个反式激活结构域，在非缺氧条件下也受到负调控（Jiang et al.1997 b; Pugh et al.1997）。这些结构域与共激活剂CBP、p300、SRC-1和TIF 2的相互作用受细胞内O2浓度和氧化还原状态的调节（Kallio et al. 1998; Ema et al. 1999; Carrero et al. 2000）。最后，还报道了人类和小鼠HIF-1 RNA的物种特异性选择性剪接（Wenger et al. 1997; Iyer et al. 1998 b; Gothie et al. 2000）。缺氧导致HIF-1在细胞核中快速积累（Wang et al.1995），在细胞核中HIF-1与HIF-1二聚化并结合核心DNA序列5-RCGTG3（Semenza 2000 a），导致VEGF和几十种其他已知靶基因的转录激活（表1）。HIF-1和HIF-1表达是小鼠胚胎存活所必需的（Kozak等1997;马尔泰佩等1997; Iyer等1998 a; Ryan等1998; 1E-MAIL www.example.com; FAX（410）955 - 0484。
Oxygen homeostasis represents an important organizing principle for human development and physiology. The essential requirement for oxidative phosphorylation to generate ATP is balanced by the risk of oxidative damage to cellular lipids, nucleic acids, and proteins. As a result, cellular and systemic O2 concentrations are tightly regulated via shortand long-acting response pathways that affect the activity and expression of a multitude of cellular proteins (for review, see Semenza 1999a). This delicate balance is disrupted in heart disease, cancer, cerebrovascular disease, and chronic obstructive pulmonary disease, which represent the most common causes of mortality and account for two-thirds of all deaths in the U.S. (Greenlee 2000). Appreciation of the fundamental importance of oxygen homeostasis for development, physiology, and disease pathophysiology is growing but still incomplete. Knowledge acquisition is presently exponential when one includes areas, such as the role of angiogenesis in ischemic or neoplastic disease, in which investigators are studying oxygen homeostasis even though they may not interpret their studies within this broad physiological context. Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis (for review, see Ferrara and Davis-Smyth 1997; Ferrara 1999). The regulation of VEGF expression illustrates how reduced O2 availability (hypoxia) can elicit physiological responses via multiple molecular mechanisms. VEGF expression is induced when most cell types are subjected to hypoxia, thus providing a mechanism by which tissue perfusion can be optimized to demand. Steady state levels of VEGF mRNA increase in hypoxic cells as a result of increased production (transcriptional activation) and decreased destruction (mRNA stabilization). Whereas overall protein synthesis is inhibited in response to hypoxia, VEGF mRNA is efficiently translated into protein by use of an internal ribosome entry site (Stein et al. 1998). Finally, expression of the VEGF receptor FLT-1 is also induced when endothelial cells are exposed to hypoxia (Gerber et al. 1997). The essential first step in this process, transcriptional activation, is mediated by the binding of hypoxia-inducible factor 1 (HIF-1) to a cis-acting hypoxia-response element located 1 kb 5 to the transcriptional start site of the human VEGF gene (Forsythe et al. 1996). HIF-1 is a basic helix–loop–helix PAS protein consisting of HIF-1 and HIF-1 subunits (Wang and Semenza 1995; Wang et al. 1995). HIF-1 expression and HIF-1 transcriptional activity are precisely regulated by cellular O2 concentration (for review, see Semenza 1999b, 2000a; Wenger 2000). The molecular mechanisms of sensing and signal transduction by which changes in O2 concentration result in changes in HIF-1 activity are poorly understood, but recent data suggest that the O2 signal is converted to a redox signal (Chandel et al. 2000; Haddad et al. 2000) that may trigger a kinase cascade and/or regulate HIF-1 directly (for review, see Semenza 1999a,b; Chandel and Schumacker 2000). The regulation of HIF-1 activity occurs at multiple levels. Whereas HIF-1 mRNA is constitutively expressed in tissue culture cells, it is markedly induced by hypoxia or ischemia in vivo (Yu et al. 1998; Bergeron et al. 1999). HIF-1 protein expression is negatively regulated in nonhypoxic cells by ubiquitination and proteasomal degradation (Salceda and Caro 1997; Huang et al. 1998; Kallio et al. 1999). Under hypoxic conditions, HIF-1 protein levels increase dramatically and the fraction that is ubiquitinated decreases (Sutter et al. 2000). Nuclear localization of HIF-1 may also be induced by hypoxia (Kallio et al. 1998). The carboxy-terminal half of HIF-1 contains two transactivation domains that are also negatively regulated under nonhypoxic conditions (Jiang et al. 1997b; Pugh et al. 1997). The interaction of these domains with the coactivators CBP, p300, SRC-1, and TIF2 is regulated by the cellular O2 concentration and redox state (Kallio et al. 1998; Ema et al. 1999; Carrero et al. 2000). Finally, species–specific alternative splicing of human and mouse HIF-1 RNA has also been reported (Wenger et al. 1997; Iyer et al. 1998b; Gothie et al. 2000). Hypoxia results in the rapid accumulation of HIF-1 in the nucleus (Wang et al. 1995) where it dimerizes with HIF-1 and binds to the core DNA sequence 5 -RCGTG3 (Semenza 2000a), leading to the transcriptional activation of VEGF and several dozen other known target genes (Table 1). HIF-1 and HIF-1 expression are required for embryonic survival in mice (Kozak et al. 1997; Maltepe et al. 1997; Iyer et al. 1998a; Ryan et al. 1998; 1E-MAIL gsemenza@jhmi.edu; FAX (410) 955-0484.