Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators

doi:10.1016/j.biocel.2004.08.012

The International Journal of Biochemistry & Cell Biology

Volume 37, Issue 3, March 2005, Pages 535-540

https://doi.org/10.1016/j.biocel.2004.08.012 Get rights and content

Abstract

Oxygen availability is crucial for cellular metabolism. Hypoxia-inducible factor 1 (HIF-1) is the major oxygen homeostasis regulator. Under normoxic conditions, HIF-1 is rapidly degraded by the proteasome. However, under hypoxic conditions, HIF-1 is stabilized and permits the activation of genes essential to cellular adaptation to low oxygen conditions. These genes include the vascular endothelial growth factor (VEGF), erythropoietin and glucose transporter-1. There is increasing evidence showing that HIF-1 is also implicated in biological functions requiring its activation under normoxic conditions. Amongst others, growth factors and vascular hormones are implicated in this normoxic activation. In this review, we will focus on differences between hypoxic and non-hypoxic induction and activation of HIF-1. We will also discuss the biological functions of HIF-1 associated with these two induction pathways. The clear understanding of both HIF-1 activation mechanisms could have a major impact in cancer and vascular disease.

Introduction

Hypoxia activates a number of genes which are important in the cellular and tissular adaptation to low oxygen conditions. If cells are unresponsive to this stressful condition, they will ultimately die. Fortunately, humans have evolved to respond quickly and efficiently to hypoxia. This elegant response is principally mediated through hypoxia-inducible factor 1 (HIF-1). HIF-1, a ubiquitously expressed heterodimeric transcription factor, was originally discovered in 1992 as being responsible for the expression of erythropoietin in hypoxic conditions. Since its discovery, more than 60 genes have been found to be induced by HIF-1 (Semenza, 2003). These genes are implicated in many different cellular functions such as cell survival, cell proliferation, apoptosis, glucose metabolism and angiogenesis.

Even if hypoxia is the main method by which HIF-1 is activated, there is an increasing body of evidence demonstrating that a number of non-hypoxic stimuli are also highly capable of turning on this transcription factor. Such stimuli include growth factors, cytokines, vascular hormones and viral proteins. Interestingly, the mechanisms that are involved in activating HIF-1 in hypoxic and non-hypoxic conditions are strikingly different. This short review will focus on these two inducers of HIF-1 and describe their relevance in HIF-mediated gene induction and associated physiological and pathophysiological implications.

Section snippets

HIF-1 protein structure

Only active as a heterodimer, HIF-1 is composed of two subunits: HIF-1α and HIF-1β (Fig. 1). While HIF-1β is readily found in cells under all oxygen conditions, HIF-1α is virtually undetectable in normal oxygen conditions. For the HIF-1 transcriptional complex to be functional, HIF-1α levels must be induced.

The human HIF-1α gene is located on chromosome 14 (14q21-q24) whereas the HIF-1β gene is located on chromosome 1 (1q21). Homology is relatively well conserved for the HIF-1α and HIF-1β

Activation of HIF-1 by hypoxia

The HIF-1α gene is constitutively expressed mainly through the action of the Sp1 transcription factor. Other binding sites for transcription factors such as AP-1 and 2, NF-1 and NF-KB are also present in the promoter region of HIF-1α gene. During hypoxia, effective protein translation of HIF-1α is maintained by the presence of an internal ribosome entry site (IRES) found in the 5′-untranslated region (5′-UTR) of the HIF-1α gene (Lang, Kappel, & Goodall, 2002). Therefore, transcription and

Activation of HIF-1 by non-hypoxic stimuli

There is accumulating evidence demonstrating that stimulation of different cell types with growth factors (Feldser et al., 1999; Richard, Berra, & Pouyssegur, 2000), cytokines (Hellwig-Burgel, Rutkowski, Metzen, Fandrey, & Jelkmann, 1999), vascular hormones (Gorlach et al., 2001, Richard et al., 2000) and viral proteins (Moon et al., 2004, Wakisaka et al., 2004) can lead to the induction and activation of HIF-1. Contrary to hypoxia, stabilization of HIF-1α does not seem to play a role in the

Biological functions of HIF-1

The mouse embryo knock-out for HIF-1α show severe cardiovascular malformations and deficiencies in neuronal development (Ryan, Lo, & Johnson, 1998). These embryos die at E10.5, and clearly demonstrate that HIF-1 is necessary for normal development. An essential adaptive response to hypoxia is necessary for survival and results from the stabilization and activation of HIF-1 and expression of cell-specific genes. The classic example is erythropoietin which is implicated in oxygen transport by

Medical applications

The role of HIF-1 in the expression of VEGF is well known. The angiogenic properties of VEGF are important but studies have shown that VEGF alone is not sufficient to promote complete and normal maturation of blood vessels. Drugs targeting mechanisms implicated in HIF-1 degradation have a major benefit of promoting the expression of many genes related to angiogenesis such as VEGF, VEGFR2, PAI-1, MMPs, EPO and IGF-2. Perfusion of cardiovascular tissue is crucial. Considerable cases of heart

Acknowledgements

Supported by grants from the Canadian Institutes of Health Research (MOP-49609), the Anemia Institute for Research and Education, les Fonds de la Recherche en Santé du Québec and the Heart and Stroke Foundations of Québec. D.E.R. is a recipient of the McDonald Scholarship from the Heart and Stroke Foundation of Canada. We would like to thank Elisabeth Pagé for her helpful comments.

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Molecules in focusHypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators

Abstract

Introduction

Section snippets

HIF-1 protein structure

Activation of HIF-1 by hypoxia

Activation of HIF-1 by non-hypoxic stimuli

Biological functions of HIF-1

Medical applications

Acknowledgements

Blood

Cell

Blood

Cancer Cell

The Journal of Biological Chemistry

The Journal of Biological Chemistry

The Journal of Biological Chemistry

HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia

The EMBO Journal

Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2

Cancer Research

Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase

Circulation Research

Molecules in focus
Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators