Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O 2 -dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1α subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1α transactivation domains is also O 2 regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1α and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1α transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1α protein stabilization and transcriptional activation in response to changes in cellular O 2 concentration.
This editorial refers to an article by Z. Cai et al . [11][1] published in Cardiovascular Research in 2008 (see [Box 1][2]). It is accompanied by an editorial by G. Heusch, pp. 214–215, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . One of the most intensively studied phenomena in cardiovascular research is ischaemic preconditioning (IPC), the observation that exposure of the heart to several short (e.g. 5 min) cycles of ischaemia (I5) and reperfusion (R5) will protect against injury caused by a subsequent prolonged (e.g. 30 min) episode of ischaemia (I30) followed by reperfusion.1 The onset of cardioprotection is immediately following the IPC stimulus and lasts for only several hours,1 but is followed by a second window of cardioprotection with the onset ∼24 h after IPC and lasting for several days thereafter.2,3 Based on thousands of research studies spanning two decades, a dominant paradigm was established that acute- or early-phase cardioprotection was rapid but short-lived because it involved transient post-translational modifications of existing proteins, whereas delayed or late-phase cardioprotection was slower to develop but longer lasting because it involved de novo synthesis of mRNAs and their translation into proteins. A remarkably long list of signal transduction pathways, biochemical reactions, and gene products have been implicated in the response of the heart to IPC.4–6 For several molecular targets, the paradigm holds: the activity of the protein is regulated during the acute phase of protection, whereas expression of the protein is regulated during the late phase. It is conventional wisdom that the IPC stimulus-response pathway is centred in cardiomyocytes. Indeed, some investigators have attempted to develop reductionist cell culture models in which cardiomyocytes are exposed to oxygen and glucose deprivation for various lengths of time,7 although others in the … [1]: #ref-11 [2]: #F2
All organisms can sense O 2 concentration and respond to hypoxia with adaptive changes in gene expression. The large body size of mammals necessitates the development of multiple complex physiological systems to ensure adequate O 2 delivery to all cells under normal conditions. The transcriptional regulator hypoxia-inducible factor 1 (HIF-1) is an essential mediator of O 2 homeostasis. HIF-1 is required for the establishment of key physiological systems during development and their subsequent utilization in fetal and postnatal life. HIF-1 also appears to play a key role in the pathophysiology of cancer, cardiovascular disease, and chronic lung disease, which represent the major causes of mortality among industrialized societies. Genetic or pharmacological modulation of HIF-1 activity in vivo may represent a novel therapeutic approach to these disorders.
Activity of hypoxia-inducible factor 1 (HIF-1) is increased in human cancers as a result of the physiological induction of HIF-1alpha in response to intratumoural hypoxia and as a result of genetic alterations that activate oncogenes and inactivate tumour suppressor genes. In many cancer types, increased HIF-1alpha expression is associated with increased risk of patient mortality. HIF-1 plays important roles in every major aspect of cancer biology through the transcriptional regulation of hundreds of genes. The efficacy of many novel anticancer agents that target signal transduction pathways may be due in part to their indirect inhibition of HIF-1. Several novel compounds with anticancer activity have been shown to inhibit HIF-1 and may be useful as components of individualised multidrug therapeutic regimens chosen based on molecular analyses of tumour biopsies.
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein implicated in the transcriptional activation of genes encoding erythropoietin, glycolytic enzymes, and vascular endothelial growth factor in hypoxic mammalian cells. In this study, we have quantitated HIF-1 DNA-binding activity and protein levels of the HIF-1 alpha and HIF-1 beta subunits in human HeLa cells exposed to O2 concentrations ranging from 0 to 20% in the absence or presence of 1 mM KCN to inhibit oxidative phosphorylation and cellular O2 consumption. HIF-1 DNA-binding activity, HIF-1 alpha protein and HIF-1 beta protein each increased exponentially as cells were subjected to decreasing O2 concentrations, with a half maximal response between 1.5 and 2% O2 and a maximal response at 0.5% O2, both in the presence and absence of KCN. The HIF-1 response was greatest over O2 concentrations associated with ischemic/hypoxic events in vivo. These results provide evidence for the involvement of HIF-1 in O2 homeostasis and represent a functional characterization of the putative O2 sensor that initiates hypoxia signal transduction leading to HIF-1 expression.
Sleep-disordered breathing with recurrent apnea is a major cause of morbidity and mortality. Affected individuals have increased risk of systemic hypertension. Sleep apnea results in chronic intermittent hypoxia (CIH). Exposure of rodents to CIH is sufficient to induce hypertension by activation of the carotid body and sympathetic nervous system, leading to increased levels of circulating catecholamines. CIH induces increased levels of reactive oxygen species (ROS), and antioxidant treatment blocks CIH-induced hypertension. The transcriptional activator hypoxia-inducible factor 1 (HIF-1) plays an essential role in O2 homeostasis. HIF-1 activity is induced when mice or cultured cells are subjected to CIH, an effect that is blocked by antioxidants. The carotid bodies from mice that are heterozygous for a null (knockout) allele at the locus encoding HIF-1 appear histologically normal but do not respond to continuous hypoxia or CIH. In contrast to wild-type littermates, when heterozygous-null mice are subjected to CIH, they do not develop hypertension or increased levels of HIF-1, catecholamines, or ROS. The data suggest the existence of a feed-forward mechanism in which CIH-induced ROS activate HIF-1, which then promotes persistent oxidative stress, which may further amplify HIF-1 activation, with its consequent effects on gene expression.
Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
