Hypoxia rapidly activates HIF-3alpha mRNA expression

FASEB J. 2003 Aug;17(11):1541-3. doi: 10.1096/fj.02-0963fje. Epub 2003 Jun 3.


The role of the hypoxia-inducible factor (HIF) subunits 1alpha and 1beta in cellular response to hypoxia is well established, whereas little is known about HIF-2alpha and HIF-3alpha with respect to organ distribution and transcriptional regulation by hypoxia. We investigated mRNA levels of all HIF subunits and of their target genes erythropoietin (EPO) and glucose-transporter 1 (GLUT1) in rats undergoing systemic hypoxia for 30 or 120 min by quantitative real-time RT-PCR. In normoxia, persistently high mRNA levels of all HIF subunits were detected in cerebral cortex, hippocampus, and lung; the heart contained the lowest amounts. Hypoxia did not affect mRNA levels of HIF-1alpha, -1beta, and -2alpha. HIF-3alpha mRNA levels increased in all organs examined after 2 h of hypoxia. A significant rise of EPO and GLUT1 mRNA levels occurred in cortex, heart, liver, and kidney after 2 h of hypoxia, indicating activation of the HIF system. Protein levels of all HIF subunits, determined in brain and lung by immunoblotting, showed a marked increase corresponding to the duration of hypoxia. Our results suggest that induction at the transcriptional level is a unique feature of HIF-3alpha, which therefore may represent a rapidly reacting component of the HIF system in protection against hypoxic damage.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Hypoxia
  • Erythropoietin / genetics
  • Erythropoietin / metabolism
  • Gene Expression Regulation
  • Glucose Transporter Type 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Kinetics
  • Male
  • Models, Genetic
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / metabolism
  • Organ Specificity
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Repressor Proteins
  • Trans-Activators / biosynthesis
  • Trans-Activators / genetics
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics


  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Glucose Transporter Type 1
  • HIF3A protein, human
  • Hif3a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Monosaccharide Transport Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Slc2a1 protein, rat
  • Trans-Activators
  • Transcription Factors
  • Erythropoietin
  • endothelial PAS domain-containing protein 1