Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-alpha subunit quantities and their associated activity are regulated in a post-translational manner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively. However, alternative modes of HIF-alpha regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-kappa B regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-kappa B directly regulates HIF-1 beta mRNA and protein. In addition, we found that NF-kappa B-mediated changes in HIF-1 beta result in modulation of HIF-2 alpha protein. HIF-1 beta overexpression can rescue HIF-2 alpha protein levels following NF-kappa B depletion. Significantly, NF-kappa B regulates HIF-1 beta (tango) and HIF-alpha (sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conserved mode of regulation. These results reveal a novel mechanism of HIF regulation, with impact in the development of novel therapeutic strategies for HIF-related pathologies including ageing, ischemia, and cancer.
- Hypoxia-inducible factor-1-Alpha
- Receptor nuclear translocator
- Aryl hydrocarbon receptor
- ARNT transcription factor
- Drosophila melanogaster
- Gene expression
- PAS protein