Hypoxia response elements

J. F. O'Rourke, G. U. Dachs, J. M. Gleadle, P. H. Maxwell, C. W. Pugh, I. J. Stratford

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Abstract

Hypoxia-inducible factor-1 (HIF-1) has been shown to mediate the transcriptional activation of its target genes in response to oxygen concentration, most likely via a pathway involving a specific oxygen sensor. Molecular cloning of HIF-1 has shown that this widely expressed, DNA binding transcription factor is a heterodimer of two proteins, HIF-la and HIF-10. A major control of HIF-1 activity by oxygen tension is achieved by changes in the level of the HIF-la subunit, which complexes with the constitutively expressed HIF-1/3 subunit. Such changes in HIF-la abundance occur via regulated stability, probably involving proteolysis, rather than at the level of transcription or translation. Further analysis has shown the existence of two separate regulatory domains in the C-terminus of the a subunit. Thus, a mechanism of oxygen-regulated HIF-1 activation is proposed, which involves the operation of one inducible domain being amplified by changes in protein level conferred by a second regulatory domain. Evidence for a critical role of HIF-1 in the response of diverse target genes involved in cellular growth and metabolism comes from studies on cultured, mutant mouse cells that lack a functional HIF-1/3 subunit. Furthermore, studies on tumor xenografts derived from the mutant and wild-type cells show that HIF-1 is activated in vivo, and has major effects on gene expression in response to tumor hypoxia. Thus, HIF-1 is a critical component of the oxygen-signaling pathway, and is a prime candidate regulator molecule for the role of coordinating vascular oxygen supply with cellular growth and energy metabolism.

Original languageEnglish
Pages (from-to)327-332
Number of pages6
JournalOncology Research
Volume9
Issue number6-7
Publication statusPublished - 1 Dec 1997

Keywords

  • Gene regulation
  • Hypoxia-inducible factor-1
  • Oxygen
  • Tumor hypoxia

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  • Cite this

    O'Rourke, J. F., Dachs, G. U., Gleadle, J. M., Maxwell, P. H., Pugh, C. W., & Stratford, I. J. (1997). Hypoxia response elements. Oncology Research, 9(6-7), 327-332.