Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Abstract

Abstract. Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated α and oxygen-insensitive β subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1α, HIF-2α, and HIF-3α, are currently known. HIF-3α differs from HIF-1α and HIF-2α in protein structure and regulation of gene expression. For a long time, HIF-3α was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1α and HIF-2α in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3α have been identified, confirming the role of HIF-3α as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature.

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-κB

“…HIF-1α, the most well-studied isoform, is ubiquitously expressed, while HIF-2α expression is restricted to endothelial cells, heart, lung, placenta and kidney [48]. Only recently the expression profile of the several HIF-3α spliced variants has been elucidated, with HIF-3α predominantly expressed in kidney and lung epithelial cells [49]. Interestingly, although HIF-1α and HIF-2α are structurally closely related, and despite some redundancy in their functions with the sharing of several common target genes, they also have distinct target gene cohorts [50].…”

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

“…1, 4 Different HIF-3 α splice variants exist, which are able to activate or repress HIF signalling depending on the cellular context. 4, 12, 13 …”

MicroRNA let‐7g possesses a therapeutic potential for peripheral artery disease

“…Several hypoxia regulated/responsive elements located in the 5 0 and 3 0 UTR of the VEGF-A gene are involved in the fine-tuning of VEGF-A expression [26]. HIF-1a and HIF-2a are transcription factors that activate VEGF-A expression, whereas HIF-3a exerts a negative regulation of the angiogenic response by competing with HIF-1a and HIF2a binding sites [16]. In the present study, we demonstrated that let7g could bind two binding sites in the HIF-3a 3…”

“…We used the IPA software to indicate that let-7g may directly bind to HIF-3a and TP53, both of which are up-stream regulators of VEGF-A [16][17][18]. The luciferase reporter assay confirmed that HIF-3a harbours two let-7g binding sites, and let-7g could dose-dependently reduce luciferase activity ( Fig.…”