ZFIN ID: ZDB-PUB-140513-380
Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia
Zhang, P., Yao, Q., Lu, L., Li, Y., Chen, P.J., Duan, C.
Date: 2014
Source: Cell Reports   6: 1110-21 (Journal)
Registered Authors: Duan, Cunming
Keywords: none
Microarrays: GEO:GSE54318
MeSH Terms:
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/metabolism*
  • Cell Hypoxia/genetics
  • Cell Hypoxia/physiology*
  • Cell Line, Tumor
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Promoter Regions, Genetic
  • Transcription, Genetic
  • Transcriptional Activation
  • Zebrafish
PubMed: 24613356 Full text @ Cell Rep.
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ABSTRACT
Hypoxia-inducible factors (HIFs) play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.
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