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