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.

Atorvastatin combined with routine therapy on HIF-1, VEGF concentration and cardiac function in rats with acute myocardial infarction

“…Hypoxia inducible factor (HIF) is a transcription factor that responds to the reduction or hypoxia of available oxygen in the cell environment (11). The HIF-1 signal cascade reaction mediates the effects of hypoxia on the cells, which typically allow the cells to differentiate continuously, promote the formation of blood vessels, and are important for the formation of a vascular system in an embryo and a tumor.…”

Correlation and expression analysis of hypoxia‑inducible factor�1α, glucose transporter 1 and lactate dehydrogenase�5 in human gastric cancer

“…Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor consisting of α (HIF-1α) and β (HIF-1β) subunits (7). HIF-1 is overexpressed and exhibits enhanced activity in the hypoxic microenvironment of tumors (8,9). Notably, the protein expression levels of HIF-1α and the binding activity of HIF-1β are upregulated during hypoxia.…”

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

“…HIF1 is activated through strict control of its alpha subunit (HIF1α) by transcription, translation, posttranslational modification like prolyl-or asparaginyl hydroxylation and ubiquitination, and microtubule-associated nuclear transportation. However, the HIF1 beta subunit (HIF1β) is constitutively expressed and does not possess an oxygen-dependent degradation domain [31][32][33][34] . Therefore, it has been suggested that HIF1α plays an important role in the HIF1-regulated metabolism.…”