Regulatory mechanisms of hypoxia-inducible factor 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 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 shown that HIF-1α may become stable and active even under normoxic conditions; for example, when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of 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.

Keywords: gene expression; hypoxia-inducible factor 1 (HIF-1); molecular mechanism; tumor hypoxia.

Figure 1

History of hypoxia‐inducible factor 1 (HIF‐1) biology in the first era. Gregg L. Semenza, William G. Kaelin, Jr, and Peter J. Ratcliffe have contributed to elucidating the molecular mechanism responsible for HIF‐1‐mediated adaptive responses to hypoxia in the first era of HIF‐1 biology. The importance of the oxygen‐dependent and ubiquitin‐mediated proteolysis of hypoxia‐inducible factor 1α (HIF‐1α) was first reported by Salceda and Caro 20 years ago in 1997.79 VHL, von Hippel‐Lindau. Images courtesy of the Albert and Mary Lasker Foundation

Figure 2

Conventional oxygen‐ and dioxygenase‐dependent regulatory mechanisms for hypoxia‐inducible factor 1 (HIF‐1) activity. FIH‐1, factor‐inhibiting HIF‐1; HIF‐1α, hypoxia‐inducible factor 1α; HIF‐1β, hypoxia‐inducible factor 1β; PHD, prolyl‐4‐hydroxylase; VHL, von Hippel‐Lindau

Figure 3

Schematic diagram showing the primary structure and hydroxylated (OH), SUMOylated (Sumo), phosphorylated (P), acetylated (Ac), nitrosylated (NO), and methylated (Me) amino acid residues of the hypoxia‐inducible factor 1α (HIF‐1α) protein. Gene symbols represented in red and blue indicate positive and negative regulators of hypoxia‐inducible factor 1 (HIF‐1), respectively. Factors are categorized into 4 groups by dashed squares according to the levels to which HIF‐1 activity is regulated; at the level of protein stability (A), interactions with hypoxia‐inducible factor 1β (HIF‐1β) (B), nuclear translocation (B), and transactivation activity (B). CK1δ, casein kinase 1δ; C‐TAD, C‐terminal transactivation domain; FIH‐1, factor‐inhibiting HIF‐1; GSK‐3, glycogen synthase kinase 3; HLH, helix‐loop‐helix; ID, inhibitory domain; IDH, isocitrate dehydrogenase; LSD1, lysine‐specific demethylase‐1; N‐TAD, N‐terminal transactivation domain; NQO1, NAD(P)H:quinone oxidoreductase 1; ODD, oxygen‐dependent degradation; PAS, Per‐Arnt‐Sim; PCAF, p300/CBP‐associated factor; PHD, prolyl‐4‐hydroxylase; PLK3, polo‐like kinase 3; RSUME, RWD‐containing SUMOylation enhancer; SDH, succinate dehydrogenase; SENP, sentrin/SUMO‐specific protease; SIRT, sirtuin