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The subtle side to hypoxia inducible factor (HIFa) regulation

Rebecca L. Bilton and Grant W. Booker

Department of Molecular Biosciences, The University of Adelaide, Australia

The transcription factor hypoxia inducible factor a-subunit

(HIFa)is pivotal in the cellular response to the stress of

hypoxia. Post-translational modification of HIFa by

hydroxylase enzymes has recently been identified as a key

oxygen sensing mechanism within the cell. The absence of

the substrate oxygen prevents the hydroxylases from modi￾fying HIFa during hypoxia and allows dramatic up-regula￾tion of both HIFa protein stability and transcriptional

activation capability. In addition to this oxygen-dependent

response, increased HIFa protein levels and/or enhanced

transcriptional activity during normoxic conditions can be

stimulated by various receptor-mediated factors such as

growth-factors and cytokines (insulin, insulin-like growth

factor 1 or 2, endothelial growth factor, tumour necrosis

factor a, angiotensin-2). Oncogenes are also capable of

HIFa activation. This induction is generally less intense than

that stimulated by hypoxia and although not fully elucida￾ted, appears to occur via hypoxia-independent, receptor￾mediated signal pathways involving either phosphatidyl

-inositol-3-kinase/Akt or mitogen activated protein kinase

(MAPK)pathways, depending on the cell-type. Activation

of Akt increases HIFa protein synthesis in the cell and results

in increased HIFa protein and transcriptional activity.

MAPK also activates HIFa protein synthesis and addi￾tionally may potentiate HIF1a transcriptional activity via a

separate mechanism that does not necessarily require protein

stabilization. Here we review the mechanisms and function

of receptor-mediated signals in the multifaceted regulation

of HIFa.

Keywords: HIFa; growth factor; oncogene; PI3K; MAPK.

Introduction

Spurred-on by the discovery of their involvement in the

pathophysiology of many disease states including cerebral

and pulmonary ischemia, cancer tumourigenesis and

malignancy [1], the bHLH-PAS domain-containing

hypoxia-inducible transcription factor (HIF)family have

become a popular focus for research in the decade since the

HIF1a gene was first characterized [2]. This family includes

the regulatory a-subunits HIF1a and HIF2a that are both

able to bind to their constitutively expressed b-subunit,

ARNT, to form a functional HIF complex. The induction

of HIFa by hypoxia (low physiological levels of oxygen)is

dramatic and has been shown to regulate the transcription

of over 40 downstream target genes, including glycolytic

enzymes, glucose transporters and vascular endothelial

growth factor [3]. Regulation of HIFa is complex and

involves multiple mechanisms of control at the level of

protein degradation and hence protein stabilization, nuclear

translocation and transcriptional activation (Fig. 1). When

stimulated by hypoxia, these mechanisms combine

co-operatively to induce maximal HIF activation. Recently

the
oxygen sensors monitoring this hypoxic response were

identified as prolyl- and asparaginyl-hydroxylase enzymes

[4–6], which during normoxia (normal physiological levels

of oxygen)mediate the rapid degradation of HIFa protein

and prevent transcriptional recruitment of the cofactor

CBP/p300, respectively. These enzymes and the mechanisms

involved in their activation of HIFa upon stimulus by

hypoxia are reviewed elsewhere [7,8].

As elucidation of the hypoxic HIFa signalling pathway

continues, another side toHIFabiology has quietly emerged.

Zelzer and coworkers [9] were the first to demonstrate that

the growth-factors insulin and insulin-like growth factor-1

(IGF-1)activate HIF1 and that this has subsequently been

shown to occur through pathways separate to that employed

by the classical hypoxic pathway (Fig. 1). The list of

Correspondence to G. Booker, Department of Molecular Biosciences,

The University of Adelaide, North Terrace, Adelaide,

SA 5005, Australia.

Fax: + 61 88303 4348, Tel.: + 61 88303 3090,

E-mail: [email protected]

Abbreviations: Akt, serine/threonine kinase (also known as protein

kinase B); ARNT, aryl-hydrocarbon receptor nuclear translocation;

bHLH-PAS, basic helix-loop-helix period-ARNT-single-minded;

CBP, CREB binding protein; CO, carbon monoxide; C-TAD,

C-terminal transcriptional activation domain; EGF, epidermal growth

factor; eIF-4E, eukaryotic initiation factor 4E; 4E-BP1, eIF-4E

binding protein 1; FGF-2, fibroblast growth factor-2; FIH-1, factor

inhibiting HIF; FRAP, FKBP(FK506 binding protein)rapamycin

associated-binding protein (also known as mTOR, mammalian target

of rapamycin); HER2NEU, heregulin-2 or EGF stimulated receptor

tyrosine kinase; HGF, hepatocyte growth factor; HIFa, hypoxia

inducible factor-1 or )2 a subunit; HRE, hypoxic response element;

IGF-1/IGF-2, insulin-like growth factor-1 or -2; IL-1b, interleukin-1b;

JNK, c-Jun amino-terminal kinase; MAPK, mitogen activated protein

kinase; MEK, MAPK kinase; NO, nitric oxide; p70S6K, p70 S6 kinase;

PDGF, platelet derived growth factor; PI3K, phosphatidyl-inositol

3-kinase; PTEN, phosphatase and tensin homolog; ROS, reactive

oxygen species; TGF-1b, transforming growth factor-1b; TNFa,

tumour necrosis factor-a; VHL, von Hippel Lindau protein.

(Received 15 October 2002, revised 6 December 2002,

accepted 3 January 2003)

Eur. J. Biochem. 270, 791–798 (2003)
FEBS 2003 doi:10.1046/j.1432-1033.2003.03446.x