Passing the baton: the HIF switch

Abstract

Hypoxia is an inadequate oxygen supply to tissues and cells, which can restrict their function. The hypoxic response is primarily mediated by the hypoxia-inducible transcription factors, HIF-1 and HIF-2, which have both overlapping and unique target genes. HIF target gene activation is highly context specific and is not a reliable indicator of which HIF-α isoform is active. For example in some cell lines, the individual HIFs have specific temporal and functional roles: HIF-1 drives the initial response to hypoxia (<24 hours) and HIF-2 drives the chronic response (>24 hours). Here, we review the significance of the HIF switch and the relationship between HIF-1 and HIF-2 under both physiological and pathophysiological conditions.

cAMP-response Element-binding Protein (CREB) and NF-κB Transcription Factors Are Activated during Prolonged Hypoxia and Cooperatively Regulate the Induction of Matrix Metalloproteinase MMP1

“…Similarly, induction profile of MMP1 may also be different between the cell types depending on the activity of CREB and NF-B. It has been reported that the activity of HIF-2 is higher than that of HIF-1 during prolonged hypoxia in certain cell lines (38,39). Therefore, CREB, NF-B, and HIF-2 might constitute a network that regulates gene expression during prolonged hypoxia (Fig.…”

Relative quantitative expression of hypoxia-inducible factor-1α, −2α and −3α, and vascular endothelial growth factor A in laryngeal carcinoma

“…Additionally, Holmquist-Mengelbier et al (30) demonstrated that HIF-1α is most active during short periods (2-24 h) of intense hypoxia or anoxia (<0.1% O 2 ), whereas HIF-2α may be active for a longer period of mild hypoxia (<5% O 2 ). This phenomenon is described in the literature as the HIF switch: HIF-1α drives the initial response to hypoxia, and HIF-2 subsequently takes over the major role during chronic hypoxic exposure (44)(45)(46). The HIF switch is particularly evident during the development of renal cell carcinoma, where there is a gradual shift from HIF-1α to HIF-2α expression with increasing tumor grade (46)(47)(48).…”

“…This phenomenon is described in the literature as the HIF switch: HIF-1α drives the initial response to hypoxia, and HIF-2 subsequently takes over the major role during chronic hypoxic exposure (44)(45)(46). The HIF switch is particularly evident during the development of renal cell carcinoma, where there is a gradual shift from HIF-1α to HIF-2α expression with increasing tumor grade (46)(47)(48). In contrast to these findings, the results of the present study display a lack of such a HIF switch in laryngeal carcinoma: Of the 7 patients with upregulated HIF-2α, 4 also exhibited an upregulation in HIF-1α levels.…”

Metabolic basis to Sherpa altitude adaptation

“…The cellular response to hypoxia is orchestrated by the hypoxia-inducible factor (HIF) transcription factors, with HIF-1α and HIF-2α, respectively, mediating responses to short-term and more sustained hypoxia (1). In normoxia, prolylhydroxylases target HIFα subunits for destruction (2).…”