• DOI:10.1074/JBC.M400461200
• Corpus ID: 83519092

Prolonged Hypoxia Differentially Regulates Hypoxia-inducible Factor (HIF)-1α and HIF-2α Expression in Lung Epithelial Cells

@article{Uchida2004ProlongedHD,
  title={Prolonged Hypoxia Differentially Regulates Hypoxia-inducible Factor (HIF)-1$\alpha$ and HIF-2$\alpha$ Expression in Lung Epithelial Cells},
  author={Tokujiro Uchida and Fabrice Rossignol and Michael A. Matthay and R{\'e}mi Mounier and Sylvianne Couette and Eric Clottes and Christine Cl{\'e}rici},
  journal={Journal of Biological Chemistry},
  year={2004},
  volume={279},
  pages={14871 - 14878}
}

• T. Uchida, Fabrice Rossignol, +4 authors C. Clérici
• Published 9 April 2004
• Biology
• Journal of Biological Chemistry

Transcriptional adaptations to hypoxia are mediated by hypoxia-inducible factor (HIF)-1, a heterodimer of HIF-α and aryl hydrocarbon receptor nuclear translocator subunits. The HIF-1α and HIF-2α subunits both undergo rapid hypoxia-induced protein stabilization and bind identical target DNA sequences. When coexpressed in similar cell types, discriminating control mechanisms may exist for their regulation, explaining why HIF-1α and HIF-2α do not substitute during embryogenesis. We report that, in a human lung epithelial cell line (A549), HIF-1α and HIF-2α proteins were similarly induced by acute hypoxia (4 h, 0.5% O2) at the translational or posttranslational level. However, HIF-1α and HIF-2α were differentially regulated by prolonged hypoxia (12 h, 0.5% O2) since HIF-1α protein stimulation disappeared because of a reduction in its mRNA stability, whereas HIF-2α protein stimulation remained high and stable. Prolonged hypoxia also induced an increase in the quantity of natural antisense HIF-1α (aHIF), whose gene promoter contains several putative hypoxia response elements to which (as we confirm here) the HIF-1α or HIF-2α protein can bind. Finally, transient transfection of A549 cells by dominant-negative HIF-2α, also acting as a dominant-negative for HIF-1α, prevented both the decrease in the HIF-1α protein and the increase in the aHIF transcript. Taken together, these data indicate that, during prolonged hypoxia, HIF-α proteins negatively regulate HIF-1α expression through an increase in aHIF and destabilization of HIF-1α mRNA. This trans-regulation between HIF-1α and HIF-2α during hypoxia likely conveys target gene specificity.