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  • Review Article
  • Published:

HIF-1 as a target for drug development

Nature Reviews Drug Discovery volume 2, pages 803–811 (2003)Cite this article

Key Points

  • The adaptation of mammalian cells to low oxygen conditions is mediated in large part by the transcriptional induction of gene expression. Hypoxia-inducible factor (HIF) is crucial in the transcriptional response of cells to hypoxia.

  • The HIF transcription factor is composed of an oxygen-labile α-subunit and a constitutively expressed β-subunit. HIF belongs to a family of heleix–loop–helix PER/SIM/ARNT (HLH-PAS) transcription factors.

  • HIF-1α stability and activity are regulated by post-translational modifications, chaperone function and alternative splicing. These pathways have generated new targets for high-throughput screening strategies.

  • In transformed cells, HIF is regulated by oncogenic and tumour-suppressor gene mutations that cause it to become stabilized under aerobic conditions.

  • HIF-1 is involved in the inflammatory response. Inhibition of HIF-1 in myeloid cells can ameliorate and even prevent inflammation, indicating a new role for HIF modulators.

  • Development of HIF-inducing compounds provides a new approach to the regulation of erythropoietin and erythropoiesis in cancer patients, of angiogenesis in cardiovascular disease and of ischaemic injury in renal patients. Small molecules that affect prolyl hydroxylation or ubiquitylation provide a prime target for such regulation.

Abstract

Sensing and responding to fluxes in oxygen tension is perhaps the single most important variable in physiology, and animal tissues have developed a number of essential mechanisms to cope with the stress of low physiological oxygen levels, or hypoxia. Among these coping mechanisms is the response mediated by the hypoxia-inducible transcription factor, or HIF-1. HIF-1 is an essential component in changing the transcriptional repertoire of tissues as oxygen levels drop, and could prove to be a very important target for drug development, as treatments evolve for diseases, such as cancer, heart disease and stroke, in which hypoxia is a central aspect.

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Figure 1: Mechanisms of HIF-1α regulation under aerobic and hypoxic conditions.
Figure 2: Signal transduction pathways implicated in HIF-1α regulation under aerobic and hypoxic conditions.
Figure 3: Examples of enzymatic steps that have been or could be targeted to inhibit HIF-1α stability or HIF-1 activity.
Figure 4: Cartoon depicting potential intracellular targets that could result in HIF-1-specific cytotoxicity.

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Acknowledgements

We apologize for any references that have not been included that have contributed to our understanding of HIF. We would like to thank all the present and past members of our laboratories that contributed to the understanding of the role of hypoxia and HIF in normal tissue homeostasis and malignant progression. The work is supported by grants from the National Cancer Institute and the Auckland Cancer Research Society.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, 94305-5468, California, USA

    Amato Giaccia

  2. Auckland Cancer Society Research Centre, University of Auckland, Private Bag, Auckland, 92019, NZ

    Bronwyn G. Siim

  3. Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, MC-0366, La Jolla, 92093-0366, California, USA

    Randall S. Johnson

Authors
  1. Amato Giaccia
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  2. Bronwyn G. Siim
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  3. Randall S. Johnson
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Correspondence to Randall S. Johnson.

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DATABASE

LocusLink

ARD1

cullin 2

EPO

HIF-1α

HIF-1αN

HIF-1β

HIF-2α

HIF-3α

HSP90

p53

PTEN

RBX1

TCEB1

TCEB2

TOR

VEGF

VHL

FURTHER INFORMATION

Encyclopedia of Life Sciences

hypoxia

Glossary

HYPOXIA-RESPONSE ELEMENT

(HRE). Initially identified as a 50-base-pair sequence in the 3′ flanking region of the erythropoietin gene. Although the core DNA binding element is 5′-ACGTG-3′, flanking sequences are also important in HRE functionality. Approximately 30 genes have been found to possess HREs.

HLH–PAS DOMAIN

HLH is a helix–loop–helix motif that facilitates dimerization and DNA binding and is found in a substantial number of transcription factors. The PAS domain was named after PER, ARNT and SIM proteins that represent the first proteins in which this motif was identified. Functionally, the PAS domain facilitates protein–protein interactions between family members.

GAL4 DNA-BINDING PROTEIN

A transcriptional activator identified in yeast, which, because it is specific for yeast, is used to make fusion proteins to study mammalian transcriptional regulators.

OXYGEN-DEPENDENT DEGRADATION

(ODD). The ODD domain of HIF-1α binds to VHL under aerobic conditions. Deletion of this domain results in a HIF-1α protein that is oxygen insensitive and constitutively expressed under aerobic conditions.

UBIQUITIN-MEDIATED DEGRADATION

The energy-requiring process of covalently linking ubiquitin to lysine residues of a substrate protein to signal protein degradation.

VON HIPPEL-LINDAU

(VHL). A tumour-suppressor gene that possesses two substrate-binding domains, -α and -β. The α-domain binds to elongin C and CUL2, proteins that possess sequence similarity with proteins known to be involved in ubiquitin-mediated degradation. The β-domain of VHL binds HIF-1α.

PROLYL HYDROXYLATION

A protein modification mediated by an evolutionarily conserved group of iron-dependent enzymes termed prolyl hydroxylases (PhDs). As they require oxygen for their activity, they have been implicated as the oxygen sensor that regulates HIF-1α stabilization. Loss of PhD activity in Caenorhabditis elegans and, more recently, in mammalian cells, has resulted in stabilization of HIF-1α under aerobic conditions.

ASPARAGINE HYDROXYLATION

This modification of HIF-1α on asparagine 803 has been implicated in the control of HIF-1 transactivation potential. The gene identified that controls this modification is termed FIH.

ACETYLATION

Acetylation has previously been implicated in promoting transcriptional activation. By contrast, acetylation of HIF-1α on lysine 532 by ARD1 has been shown to be involved in its degradation by the proteasome.

DEHYDROXYLASE

An enzyme that can remove the hydroxyl group from proline 564 and promote HIF-1α stabilization.

DEUBIQUITINASE

An enzyme that promotes the removal of ubiquitin from a substrate protein such as HIF-1α through the cleavage of isopeptide bonds. The enzymatic activity of a HIF-1α deubiquitinase should increase HIF-1α stabilization.

HYPOXIA-SPECIFIC CYTOTOXIN

A molecule whose cytotoxic activity is inhibited under aerobic conditions and increased under hypoxic conditions.

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Giaccia, A., Siim, B. & Johnson, R. HIF-1 as a target for drug development. Nat Rev Drug Discov 2, 803–811 (2003). https://doi.org/10.1038/nrd1199

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