Elsevier

Cellular Signalling

Volume 17, Issue 1, January 2005, Pages 1-9
Cellular Signalling

Review
Signalling via the hypoxia-inducible factor-1α requires multiple posttranslational modifications

https://doi.org/10.1016/j.cellsig.2004.04.010Get rights and content

Abstract

Cellular hypoxia, a local decrease in the oxygen concentration below normal (21%) atmospheric concentrations, occurs in both physiological and pathological situations. The transcriptional complex Hypoxia-Inducible Factor-1 (HIF-1) is the key player in the signalling pathway that controls the hypoxic response of mammalian cells. Tight regulation of this response involves posttranslational modification of the alpha subunit of HIF-1. Hydroxylation, ubiquitination, acetylation, S-nitrosation and phosphorylation have been shown to determine its half-life and/or transcriptional activity. The precise spatio-temporal occurrence of these multiple modifications is still not fully understood but is dependent on the microenvironment and determines the driving force of variable cellular responses.

Introduction

The transcription factor, Hypoxia-Inducible Factor-1 (HIF-1), is the key component responsible for the induction under hypoxic, low oxygen, conditions of over 70 genes (for review see Ref. [1]). This factor is composed of a constitutively expressed β subunit and an α subunit that is rapidly degraded under normoxic (21% O2) conditions but stable under hypoxic conditions. These proteins belong to the basic helix-loop-helix (bHLH)–PER-ARNT-SIM (PAS) protein family (Fig. 1). Three isoforms of the α subunit of the transcription factor HIF have been identified: HIF-1α, -2α (also referred to as EPAS-1, MOP2, HLF, and HRF) and -3α. HIF-1α is the best characterized and forms a heterodimer with the HIF-1β subunit, initially identified as the Aryl hydrocarbon Receptor Nuclear Translocator (ARNT). HIF-2α and 3α compete for binding to ARNT. Under hypoxic conditions HIF-1α translocates to the nucleus, a process that is mediated by specific basic sequences on the protein termed nuclear localisation signals. Two transactivation (stimulation of transcription) domains, N-terminal (N-TAD) and C-terminal (C-TAD), in the C-terminal half of the HIF-1α protein have been identified. The C-TAD in particular has been shown to interact with co-activators including p300/CBP to activate transcription. Transactivation of target genes involves dimerization of the two subunits and binding to an enhancer element termed the Hypoxia-Response Element (HRE) in target genes. The bHLH and PAS motifs are required for dimerization while the downstream basic region affords specific binding to the HRE DNA sequence 5′-RCGTG-3′. The stability and subsequent transactivational function of the α subunit of HIF-1 is regulated by its posttranslational modification, in particular hydroxylation and phosphorylation. It has been shown that hydroxylation of HIF-1α on two proline residues by oxygen-dependent proly-4-hydroxylases is the signal for interaction with the E3 ubiquitin ligase, von Hippel-Lindau protein (pVHL), and subsequent polyubiquitination and degradation of HIF-1α by the proteosomal system. In addition, hydroxylation of an asparagine residue in the C-terminal transactivation domain of HIF-1α leads to inactivation of its transcriptional activity by precluding the binding of the co-activator p300/CBP [2].

A substantial number of excellent reviews on the biology of the cellular response to hypoxia and of the HIF-1 signalling pathway have been published in the last 10 years. In the last year, 2003, we can cite at least nine [3], [4], [5], [6], [7], [8], [9], [10], [11]. This reflects the growing interest that this research field attracts mainly because of the realization that hypoxia, be it partial or severe, has a strong impact, via gene expression, on cell biology and mammalian physiology. Keeping this in mind, we have attempted to concentrate on recent revelations and review aspects that are of parallel interest to the functioning of the HIF-1 pathway. We will focus in particular on recent advances made in the understanding of the different posttranslational modifications that the HIF-1 protein is subjected to and the mechanisms by which these modifications regulate the fine-tuning of HIF-1 function.

Section snippets

Posttranslational modification as a switch in function

The level of complexity of a particular species cannot be entirely explained by the number of genes a particular organism possesses. This is one conclusion that may be drawn from genome sequencing data. Additional posttranscriptional and posttranslational modifications may help to explain the phenotype differences, for example between chimpanzees and humans whose genomic DNA sequences are so highly conserved. The regulation of the profile of gene transcription in different tissues of eukaryotes

Conclusion

The HIF-1α protein is an excellent example of multiple posttranslational modifications as switches in function. While the consequence of these different modifications is becoming clear, the interplay between them is still to be defined (Fig. 4).

The acetylation of the HIF-1α protein occurs on a lysine residue and since lysine residues may undergo other forms of modification including ubiquitination, SUMOylation and methylation, it is possible to envisage that under the influence of a specific

Acknowledgements

We thank the members of the Pouysségur laboratory for sharing with us some of their unpublished results and comments. We apologize to the many research groups whose work was cited indirectly by reference to review articles; the limitation in length of this review does not allow us to cite all the pertinent individual studies. Our laboratory is funded by grants from the Ligue National Contre le Cancer (Equipe labellisée), the Centre National de la Recherche Scientifique (CNRS) and the Ministère

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