Tài liệu Báo cáo khoa học: Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and

REVIEW ARTICLE

Oxygen-dependent regulation of hypoxia-inducible factors by prolyl

and asparaginyl hydroxylation

David Lando1

, Jeffrey J. Gorman2,*, Murray L. Whitelaw1 and Daniel J. Peet1

1

Department of Molecular BioSciences (Biochemistry) and the Centre for Molecular Genetics of Development,

University of Adelaide, Australia; 2

CSIRO Health Sciences and Nutrition, Parkville, Victoria, Australia

To sustain life mammals have an absolute and continual

requirement for oxygen, which is necessary to produce

energy for normal cell survival and growth. Hence, main￾tainingoxygen homeostasis is a critical requirement and

mammals have evolved a wide range of cellular and phy￾siological responses to adapt to changes in oxygen avail￾ability. In the past few years it has become evident that the

transcriptional protein complex hypoxia-inducible factor

(HIF) is a key regulator of these processes. In this review we

will focus on the way oxygen availability regulates HIF

proteins and in particular we will discuss the way oxygen￾dependent hydroxylation of specific amino acid residues has

been demonstrated to regulate HIF function at the level of

both protein stability and transcriptional potency.

Keywords: oxygen sensing; hypoxia; hydroxylation;

transcriptional regulation; hypoxia-inducible factor (HIF).

Introduction

The development of complex cardiovascular, respiratory

and hemopoietic systems in mammals provides a means to

efficiently capture and deliver oxygen (O2) from the

environment to every cell of the body. While a sufficient

supply of oxygen is essential for energy production, too

much oxygen in the form of free radicals (i.e. superoxide,

OH–

) can be detrimental [1]. Therefore to maximize oxygen

use, as well as at the same time minimize the impact of

oxygen free radicals, cells have developed mechanisms to

maintain oxygen concentrations within a narrow

physiological range. To achieve this mammals regulate

oxygen consumption and levels by a combination of both

cellular and systemic processes. For example, when oxygen is

limiting(hypoxia) individual cells decrease oxidative phos￾phorylation and rely on glycolysis as the primary means of

ATP production. To facilitate this switch to glycolysis cells

up-regulate the expression of a select set of genes, such as

those encoding glycolytic enzymes and glucose transporters

[2]. Other hypoxic responses monitor global oxygen levels

and effect system wide changes in tissue oxygen availability.

For instance, the hypoxic induction of the hormone

erythropoietin (Epo) by the kidney stimulates red blood cell

production to increase the oxygen carrying capacity of the

blood [2]. Tissues and cells experiencingreduced oxygen

supply, like those associated with wound healing, increase

the levels of the angiogenic cytokine vascular endothelial

growth factor (VEGF). VEGF then acts on endothelial cells

to stimulate the proliferation of new blood vessels, which in

turn help maintain an adequate supply of oxygen [3].

However, in many disease states such as cancer, stroke and

heart attack these same oxygen delivery systems can become

misregulated and hypoxia becomes a major component of

the pathophysiology of these diseases [4].

For many years the Epo system was used to study the

molecular mechanisms associated with the induction of

hypoxia responsive genes and from these investigations the

hypoxia-inducible factor (HIF) was identified as a key

transcriptional hypoxic regulator of Epo [5,6]. Subsequent

research has now found that a large number of other

hypoxia-inducible genes (Fig. 1) are also induced by HIF

under hypoxic conditions, revealingthat HIF functions as a

master transcriptional regulator of the adaptive response to

hypoxia [7–53].

Hypoxia-inducible factor

The HIF transcriptional complex is a heterodimer consist￾ingof one of three alpha subunits (HIF-1a, HIF-2a or

HIF-3a) and a beta subunit called ARNT [6,54–57].

Correspondence to D. J. Peet, Department of Molecular

BioSciences (Biochemistry) and the Centre for Molecular Genetics

of Development, University of Adelaide, Adelaide, South Australia,

5005 Australia. Fax: + 61 8 8303 4348,

E-mail: [email protected]

Abbreviations: ARNT, aryl hydrocarbon nuclear translocator;

bHLH, basic helix-loop-helix; CAD, carboxy-terminal transactivation

domain; CBP, CREB bindingprotein; CH, cysteine-histidine;

CO, carbon monoxide; CREB, cyclic AMP-response element binding

protein; DMOG, dimethyloxalylglycine; Dsfx, desferrioxamine;

Epo, erythropoietin; FIH-1, factor inhibitingHIF-1; HIF, hypoxia￾inducible factor; HPH, HIF prolyl-4-hydroxylase; MAPK, mitogen

activated protein kinase; NAD, amino-terminal transactivation

domain; NO, nitric oxide; ODD, oxygen-dependent degradation

domain; PAS, Per-ARNT-Sim; PHD, prolyl hydroxylase

domain-containingprotein; RLL, arginine-dileucine; VEGF, vascular

endothelial growth factor; VHL, von Hippel-Lindau.

*Present address: Institute for Molecular Bioscience, University of

Queensland, St Lucia, Queensland, 4067, Australia.

(Received 15 October 2002, revised 13 December 2002,

accepted 3 January 2003)

Eur. J. Biochem. 270, 781–790 (2003)
FEBS 2003 doi:10.1046/j.1432-1033.2003.03445.x