Evolutionary conserved regulation of HIF-1 beta by NF-kappa B

Patrick van Uden, Niall S. Kenneth, Ryan Webster, H. Arno Muller, Sharon Mudie, Sonia Rocha (Lead / Corresponding author)

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    Abstract

    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.

    Original languageEnglish
    Article numbere1001285
    Pages (from-to)-
    Number of pages15
    JournalPLoS Genetics
    Volume7
    Issue number1
    DOIs
    Publication statusPublished - Jan 2011

    Keywords

    • Hypoxia-inducible factor-1-Alpha
    • Receptor nuclear translocator
    • Aryl hydrocarbon receptor
    • ARNT transcription factor
    • Drosophila melanogaster
    • Gene expression
    • PAS protein
    • Defects
    • Oxygen
    • HIF-1-Alpha

    Cite this

    van Uden, P., Kenneth, N. S., Webster, R., Muller, H. A., Mudie, S., & Rocha, S. (2011). Evolutionary conserved regulation of HIF-1 beta by NF-kappa B. PLoS Genetics, 7(1), -. [e1001285]. https://doi.org/10.1371/journal.pgen.1001285