Evolutionary conserved regulation of HIF-1β by nf-κb

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. © 2011 van uden et al.