Regulatory mechanisms of HIF-1 activity: Two decades of knowledge

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors, and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of the oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has revealed that HIF-1α may become stable and active, even under normoxic conditions; e.g. when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of the oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

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