Hypoxia response elements.

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-1 alpha and HIF-1 beta. A major control of HIF-1 activity by oxygen tension is achieved by changes in the level of the HIF-1 alpha subunit, which complexes with the constitutively expressed HIF-1 beta subunit. Such changes in HIF-1 alpha 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 alpha 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 beta 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.