HIF1? protein stability is increased by acetylation at lysine 709.

ABSTRACT: Lysine acetylation regulates protein stability and function. p300 is a component of the HIF-1 transcriptional complex and positively regulates the transactivation of HIF-1. Here, we show a novel molecular mechanism by which p300 facilitates HIF-1 activity. p300 increases HIF-1? (HIF1?) protein acetylation and stability. The regulation can be opposed by HDAC1, but not by HDAC3, and is abrogated by disrupting HIF1?-p300 interaction. Mechanistically, p300 specifically acetylates HIF1? at Lys-709, which increases the protein stability and decreases polyubiquitination in both normoxia and hypoxia. Compared with the wild-type protein, a HIF1? K709A mutant protein is more stable, less polyubiquitinated, and less dependent on p300. Overexpression of the HIF1? wild-type or K709A mutant in cancer cells lacking the endogenous HIF1? shows that the K709A mutant is transcriptionally more active toward the HIF-1 reporter and some endogenous target genes. Cancer cells containing the K709A mutant are less sensitive to hypoxia-induced growth arrest than the cells containing the HIF1? wild-type. Taken together, these data demonstrate a novel biological consequence upon HIF1?-p300 interaction, in which HIF1? can be stabilized by p300 via Lys-709 acetylation.

SUBMITTER: Geng H 

PROVIDER: S-EPMC3471753 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature