HIF-1 and mechanisms of hypoxia sensing

doi:10.1016/S0955-0674(00)00194-0

Current Opinion in Cell Biology

Volume 13, Issue 2, 1 April 2001, Pages 167-171

https://doi.org/10.1016/S0955-0674(00)00194-0 Get rights and content

Abstract

Hypoxia-inducible factor 1 (HIF-1) is an oxygen-regulated transcriptional activator that plays essential roles in mammalian development, physiology and disease pathogenesis. The HIF-1α subunit is subjected to oxygen-dependent ubiquitination and proteasomal degradation that is mediated by the von Hippel-Lindau protein. Interaction of HIF-1α transactivation domains with coactivators is induced by hypoxia. The signal transduction pathway remains enigmatic, but involves generation of reactive oxygen species. Nitric oxide induces HIF-1α under non-hypoxic conditions but inhibits hypoxia-induced HIF-1α expression.

Introduction

Although maintenance of oxygen homeostasis is an essential cellular and systemic function, it is only within the past several years that the molecular mechanisms underlying this fundamental aspect of cell biology have begun to be elucidated and their connections to development, physiology and pathophysiology have been established. Most basic cellular processes are modulated by the cellular oxygen concentration and a recent study suggests that important aspects of cell biology may be misinterpreted by performing studies under a non-physiologic (ambient) oxygen concentration 1 radical dot .

This review will focus on HIF-1 (hypoxia-inducible factor 1), the transcriptional activator that functions as a master regulator of oxygen homeostasis. Recent advances in delineating upstream signal transduction pathways leading to the induction of HIF-1 activity and expression of downstream target genes that mediate its physiologic effects will be summarized. Among the recent major advances in this field are the discoveries of the role of reactive oxygen species (ROS) in hypoxia signal transduction; the role of ubiquitination in regulating HIF-1 activity; the regulation of HIF-1 activity by signals other than hypoxia, including nitric oxide (NO), cytokines and growth factors; and the involvement of HIF-1 in embryonic development, physiologic responses to hypoxia and the pathophysiology of common causes of mortality in the developed world, including heart attack, stroke, cancer and chronic lung disease. Here, the molecular mechanisms involved in the oxygen-dependent regulation of HIF-1 induction will be discussed. The physiologic and pathological consequences of HIF-1 induction have been reviewed recently 2.

Section snippets

HIF-1 structure, function and regulation

HIF-1 is a heterodimer composed of HIF-1α and HIF-1β subunits (3; Fig. 1). Whereas HIF-1β is constitutively expressed, HIF-1α expression is induced in hypoxic cells with an exponential increase in expression as cells are exposed to O₂ concentrations of less than 6% 4, which corresponds to a partial pressure (P) of O₂ of approximately 40 mm Hg at sea level. Several dozen HIF-1-regulated target genes have been identified that play essential roles in cellular and systemic physiologic responses to

Hypoxia signal transduction

The molecular mechanisms by which mammalian cells sense hypoxia and transduce this signal to HIF-1α have remained enigmatic 26. Recent studies have provided experimental evidence in support of the hypothesis that mitochondrial generation of superoxide and, subsequently, hydrogen peroxide are required for induction of HIF-1 activity and transcription of downstream target genes in hypoxic cells 27, 28, 29, 30, 31. This model thus proposes that ROS generation increases under hypoxic conditions,

Conclusions

HIF-1 is a master regulator of oxygen homeostasis that plays critical roles in a multitude of developmental and physiologic processes. Several dozen HIF-1 target genes have been identified to date that participate in responses to hypoxia 2, but these genes are unlikely to represent more than 10% of the total number that will eventually be identified by gene-expression profiling using DNA microarrays. Both the expression of HIF-1α and its transcriptional activity are modulated by the cellular O₂

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest
of outstanding interest

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ReviewHIF-1 and mechanisms of hypoxia sensing

Abstract

Introduction

Section snippets

HIF-1 structure, function and regulation

Hypoxia signal transduction

Conclusions

References and recommended reading

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HIF-1 and human disease: one highly involved factor

Genes Dev

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension

Proc Natl Acad Sci USA

Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension

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Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway

Proc Natl Acad Sci USA

HIF-1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations

Proc Natl Acad Sci USA

Review
HIF-1 and mechanisms of hypoxia sensing

Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension

Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O₂ tension

Regulation of hypoxia-inducible factor 1α is mediated by an O₂-dependent degradation domain via the ubiquitin-proteasome pathway