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van Uden, P., Kenneth, N.S., Webster, R., Müller, H.A., Mudie, S., Rocha, S. (2011). Evolutionary Conserved Regulation of HIF-1β by NF-κB.  PLoS Genet. 7(1): e1001285.
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Research paper

Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-α 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-α regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-κB regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-κB directly regulates HIF-1β mRNA and protein. In addition, we found that NF-κB-mediated changes in HIF-1β result in modulation of HIF-2α protein. HIF-1β overexpression can rescue HIF-2α protein levels following NF-κB depletion. Significantly, NF-κB regulates HIF-1β (tango) and HIF-α (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.

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PubMed Central ID
PMC3029248 (PMC) (EuropePMC)
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    Publication Type
    PLoS Genet.
    PLoS Genetics
    Publication Year
    1553-7404 1553-7390
    Data From Reference
    Aberrations (1)
    Alleles (7)
    Genes (10)
    Transgenic Constructs (2)