Aufsatz in einer Fachzeitschrift
Evolutionary Conserved Regulation of HIF-1 beta by NF-kappa B
Details zur Publikation
Autor(inn)en: | van Uden, P.; Kenneth, N.; Webster, R.; Müller, H.; Mudie, S.; Rocha, S. |
Verlag: | PUBLIC LIBRARY SCIENCE |
Publikationsjahr: | 2011 |
Zeitschrift: | PLoS Genetics |
Seitenbereich: | e1001285 |
Jahrgang/Band : | 7 |
Heftnummer: | 1 |
Seitenumfang: | 15 |
ISSN: | 1553-7390 |
eISSN: | 1553-7404 |
DOI-Link der Erstveröffentlichung: |
Zusammenfassung, 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.
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.
