Review
Hypoxia-dependent activation of HIF into a transcriptional regulator

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Abstract

Adaptation to conditions of limited oxygen availability (hypoxia) is a critical determinant of cell and tissue viability in several physiological and pathophysiological conditions. The hypoxia-inducible factor (HIF) is an oxygen-sensitive transcriptional activator that, under hypoxia, upregulates the expression of genes involved in the control of glucose metabolism, angiogenesis and cellular proliferation, among others. Activation of HIF to a fully competent transcriptional regulatory protein complex is a multi-step process that involves control of protein stability, subcellular localization, DNA-binding and interaction with transcriptional coregulators. The identity, regulation and hierarchy of interactions between several components of the HIF signal transduction pathway has been the object of intense study over the past decade and will be the subject of this review. Particular emphasis is given to the process of coordinated coactivator recruitment within the cell nucleus. The implications for future development of angiogenic/antiangiogenic therapeutic strategies of HIF activation/inactivation are discussed.

Introduction

Throughout evolution, it is evident that most higher eukaryotes have developed a variety of strategies to adapt to the increase in animal size, complexity and metabolic functions, in an atmosphere with increasing oxygen levels (up to the 21% O2 observed in modern times). The necessity to maintain a careful balance between the amount of oxygen to be delivered to a specific cell or tissue and the need to avoid generation of toxic reactive oxygen species by excess oxygen supply, has driven the development of several efficient mechanisms of homeostasis, both at the systemic and cellular level. Oxygen is used by cells not only for mitochondrial ATP production but also as a substrate in a large number of enzymatic reactions that can be strongly affected by local changes in pO2 [1]. For these reasons, in a poorly oxygenated environment (hypoxia), cell and tissue viability depends on the activation of several molecular processes that will ultimately lead to changes in protein activity and gene expression [2]. One of the primary targets for oxygen-dependent regulation is the transcriptional activator hypoxia-inducible factor-1 (HIF-1) [3], [4]. This transcriptional activator is tightly regulated by cellular oxygen levels and is strictly necessary for the activation of a network of genes that encode for proteins needed to maintain tissue viability by adjusting cell metabolism (glucose transporters, glycolytic enzymes), erythropoiesis (erythropoietin), vasomotor control (endothelin-1), angiogenesis (vascular endothelial growth factor (VEGF)) and tissue remodeling (placental growth factor (PLGF)) [5]. The activation of HIF to its fully competent form, able to bind specific DNA consensus sequences (hypoxia-response elements or HREs) present in the regulatory regions of target genes and recruit the necessary coactivator proteins to initiate transcription, is achieved through a series of events that will be the focus of this review.

In this step-wise activation process, several oxygen-dependent enzymatic activities have been identified that act on specific HIF-1 amino acid residues (summarized in Table 1). These post-translational modifications dictate the formation of different HIF-1-associated protein complexes involved in the control of protein stability, subcellular compartmentalization and transactivation function of this transcription factor.

Section snippets

HIF-1 subunit composition, structure and function

HIF-1 is a heterodimer formed by two members of the basic helix–loop–helix (bHLH)/PER–ARNT–SIM (PAS) family of transcription factors: HIF-1α and ARNT (also termed HIF-1β) (Fig. 1). ARNT is the previously characterized aryl hydrocarbon receptor nuclear translocator that can serve as DNA-binding partner for other bHLH/PAS proteins such as the aryl hydrocarbon receptor (AhR) or the single minded proteins (SIM-1 and SIM-2) [6]. HIF-1α is the oxygen-regulated subunit, which has been the subject of

HIF-1 regulation by control of protein stability

Oxygen levels do not seem to significantly affect the activity of ARNT as a transcription factor, which is constitutively expressed and localized to the nuclear compartment due to an N-terminal nuclear localization signal (NLS) [17]. Hypoxia may, however indirectly, limit the availability of ARNT as a dimerization partner in the cell nucleus, since at low oxygen concentrations the ARNT–HIF-α combination seems to be favored above all others due to the dominating affinity of HIF-1α for ARNT [18].

HIF-1-mediated activation of transcription

Stabilization of HIF-1α is the first step in a cascade of events that will ultimately lead to the recruitment of a variety of proteins involved in the activation of transcription of hypoxia-inducible genes, the products of which will participate in the adaptation to the hypoxic environment. In eukaryotic cells, transcriptional activation mechanisms are complex events that depend on the modulation of the amount, activity and localization of many proteins through post-translational modification,

Subcellular compartmentalization and HIF regulation

The use of fluorescence microscopy together with green fluorescent protein (GFP) and GFP-related technologies has led to the identification of another important level of regulation in the HIF signaling pathway. Several studies focused on the subcellular distribution of proteins involved in HIF regulation have shown that compartmentalization of several HIF partner proteins (e.g. HIF-1α, PHDs, FIH-1) participates in the modulation of their overall activity. The intracellular redistribution of

HIF-1-dependent transactivation in a cell- or promoter-specific context

Although HIF-1 is ubiquitously expressed and activated by hypoxia [80], the pattern of tissue-specific expression of HIF-1 target genes, such as erythropoietin (Epo), is not altered upon activation. Epo is expressed in the kidney and liver in a hypoxia-inducible manner, which is mediated by an enhancer situated in the 3′ region of the gene [81]. Early observations determined that binding of HIF-1 to an HRE present in the 3′ enhancer was critical for Epo induction under hypoxia [3]. It was

Acknowledgement

We thank the members of the Poellinger lab for critical review and suggestions.

References (95)

  • P.J. Kallio et al.

    Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin–proteasome pathway

    J Biol Chem

    (1999)
  • M.E. Cockman et al.

    Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein

    J Biol Chem

    (2000)
  • A.C. Epstein et al.

    C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation

    Cell

    (2001)
  • K. Nakayama et al.

    Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia

    Cell

    (2004)
  • S. Malik et al.

    Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells

    Trends Biochem Sci

    (2000)
  • J.W. Conaway et al.

    The mammalian Mediator complex

    FEBS Lett

    (2005)
  • S.S. Koh et al.

    Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities

    J Biol Chem

    (2001)
  • G.L. Cuthbert et al.

    Histone deimination antagonizes arginine methylation

    Cell

    (2004)
  • W. Fischle et al.

    Histone and chromatin cross-talk

    Curr Opin Cell Biol

    (2003)
  • R.G. Roeder

    Transcriptional regulation and the role of diverse coactivators in animal cells

    FEBS Lett

    (2005)
  • T. Pereira et al.

    Identification of residues critical for regulation of protein stability and the transactivation function of the hypoxia-inducible factor-1alpha by the von Hippel-Lindau tumor suppressor gene product

    J Biol Chem

    (2003)
  • V. Srinivas et al.

    Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins

    Biochem Biophys Res Commun

    (1999)
  • J. Huang et al.

    Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3

    J Biol Chem

    (2002)
  • J.L. Ruas et al.

    Functional analysis of hypoxia-inducible factor-1 alpha-mediated transactivationIdentification of amino acid residues critical for transcriptional activation and/or interaction with CREB-binding protein

    J Biol Chem

    (2002)
  • J. Gu et al.

    Molecular mechanism of hypoxia-inducible factor 1alpha–p300 interactionA leucine-rich interface regulated by a single cysteine

    J Biol Chem

    (2001)
  • I.M. Yasinska et al.

    S-nitrosation of Cys-800 of HIF-1alpha protein activates its interaction with p300 and stimulates its transcriptional activity

    FEBS Lett

    (2003)
  • K. Gradin et al.

    The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine

    J Biol Chem

    (2002)
  • K.S. Hewitson et al.

    Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family

    J Biol Chem

    (2002)
  • S.K. Zaidi et al.

    Intranuclear trafficking: organization and assembly of regulatory machinery for combinatorial biological control

    J Biol Chem

    (2004)
  • U. Roth et al.

    The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway

    J Biol Chem

    (2004)
  • Y. Makino et al.

    Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus

    J Biol Chem

    (2002)
  • A.L. Kung et al.

    Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway

    Cancer Cell

    (2004)
  • D. Lando et al.

    A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1alpha and the HIF-like factor

    J Biol Chem

    (2000)
  • J.W. Jeong et al.

    Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation

    Cell

    (2002)
  • J.M. Vanderkooi et al.

    Oxygen in mammalian tissue: methods of measurement and affinities of various reactions

    Am J Physiol

    (1991)
  • G.L. Wang et al.

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

    Proc Natl Acad Sci USA

    (1995)
  • M.C. Lindebro et al.

    Protein–protein interaction via PAS domains: role of the PAS domain in positive and negative regulation of the bHLH/PAS dioxin receptor–Arnt transcription factor complex

    EMBO J

    (1995)
  • I. Pongratz et al.

    Role of the PAS domain in regulation of dimerization and DNA binding specificity of the dioxin receptor

    Mol Cell Biol

    (1998)
  • P.J. Erbel et al.

    Structural basis for PAS domain heterodimerization in the basic helix–loop–helix–PAS transcription factor hypoxia-inducible factor

    Proc Natl Acad Sci USA

    (2003)
  • R.H. Wenger et al.

    The mouse gene for hypoxia-inducible factor-1alpha—genomic organization, expression and characterization of an alternative first exon and 5′ flanking sequence

    Eur J Biochem

    (1997)
  • K. Sogawa et al.

    Possible function of Ah receptor nuclear translocator (Arnt) homodimer in transcriptional regulation

    Proc Natl Acad Sci USA

    (1995)
  • H.P. Ko et al.

    Dioxin-induced CYP1A1 transcription in vivo: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure

    Mol Cell Biol

    (1996)
  • K. Gradin et al.

    Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor

    Mol Cell Biol

    (1996)
  • P.J. Kallio et al.

    Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha

    EMBO J

    (1998)
  • P.J. Kallio et al.

    Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor

    Proc Natl Acad Sci USA

    (1997)
  • L.E. Huang et al.

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

    Proc Natl Acad Sci USA

    (1998)
  • P.H. Maxwell et al.

    The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

    Nature

    (1999)
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