Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain.

ABSTRACT: The ubiquitin-proteasome pathway (UPP) is involved in regulation of multiple cellular processes. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a prototypic target of the UPP and, as such, is stabilized under conditions of proteasomal inhibition. Using carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) expression as paradigmatic markers of HIF-1 activity, we found that proteasomal inhibitors (PI) abrogated hypoxia-induced CAIX expression in all cell lines tested and VEGF expression in two out of three. Mapping of the inhibitory effect identified the C-terminal activation domain (CAD) of HIF-1 alpha as the primary target of PI. PI specifically inhibited the HIF-1 alpha CAD despite activating the HIF-1 alpha coactivator p300 and another p300 cysteine/histidine-rich

SUBMITTER: Kaluz S 

PROVIDER: S-EPMC1592766 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature