The human HIF (hypoxia-inducible factor)-3α gene is a HIF-1 target gene and may modulate hypoxic gene induction

Abstract

HIF (hypoxia-inducible factor)-3alpha is the third member of the HIF transcription factor family. Whereas HIF-1alpha and -2alpha play critical roles in the cellular and systemic adaptation to hypoxia, little is known about the regulation and function of HIF-3alpha. At least five different splice variants may be expressed from the human HIF-3alpha locus that are suggested to exert primarily negative regulatory effects on hypoxic gene induction. In the present paper, we report that hypoxia induces the human HIF-3alpha gene at the transcriptional level in a HIF-1-dependent manner. HIF-3alpha2 and HIF-3alpha4 transcripts, the HIF-3alpha splice variants expressed in Caki-1 renal carcinoma cells, rapidly increased after exposure to hypoxia or chemical hypoxia mimetics. siRNA (small interfering RNA)-mediated HIF-alpha knockdown demonstrated that HIF-3alpha is a specific target gene of HIF-1alpha, but is not affected by HIF-2alpha knockdown. In contrast with HIF-1alpha and HIF-2alpha, HIF-3alpha is not regulated at the level of protein stability. HIF-3alpha protein could be detected under normoxia in the cytoplasm and nuclei, but increased under hypoxic conditions. Promoter analyses and chromatin immunoprecipitation experiments localized a functional hypoxia-responsive element 5' to the transcriptional start of HIF-3alpha2. siRNA-mediated knockdown of HIF-3alpha increased transactivation of a HIF-driven reporter construct and mRNA expression of lysyl oxidase. Immunohistochemistry revealed an overlap of HIF-1alpha-positive and HIF-3alpha-positive areas in human renal cell carcinomas. These findings shed light on a novel aspect of HIF-3alpha as a HIF-1 target gene and point to a possible role as a modulator of hypoxic gene induction.

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

“…Li and colleagues later reported that HIF-3a is abundantly expressed in lung epithelial cells, and that the stimulation of HIF-3a-dependent transcription is important for the response to hypoxia in vitro (17). Tanaka and colleagues also showed that HIF-3a is a HIF-1a target gene, suggesting a possible role for HIF-3a in hypoxiaassociated gene expression (24).…”

Hypoxia-inducible Factors and the Prevention of Acute Organ Injury

“…Enhanced levels of PHD-3 were traced in the hibernating myocardium [34] and in end-stage heart failure in humans, associated also with elevated HIF-3α [46] (which may act as a competitive inhibitor of active HIF-α isoforms [14]). Th us, PHD inhibitors may conceivably also be benefi cial in these disorders.…”

“…Recent discoveries underscore a host of additional compound biological pathways, associated with the regulation of the HIF signal, including the control of HIF synthesis, HIF controlling PHD synthesis, putative competing/intervening impacts of HIF-3α and PHD-3, cross-talk of HIF and other key regulators of gene expression (STAT, p-300 and others), further modifi cation of HIF-α activity at the level of DNA hypoxiaresponsive elements by small ubiquitin-like modifi ers (SUMO) and factor inhibiting HIF (FIH), and the eff ect of reactive oxygen species (ROS), NO and Krebs cycle metabolites on HIF degradation. Th ese complex pathways are beyond the scope of this review, and the interested reader is referred to additional references [3,5,[12][13][14][15][16][17][18].…”

The Role of Hypoxia-Inducible Factors in Cancer Resistance

“…Autophagy HEAK293T [112] ANGPTL4 Erythropoiesis MDA-MB-231 cells [95] HIF3α Transcription factor RCC [59] NDRG …”

“…HIF3α-8 lacks only the bHLH domain and has 613 aminoacid residues. HIF3α-10 retains only the intron 1, so it encodes a 7 aminoacid peptide [26,58,59]. …”