Format

Send to

Choose Destination
Sci Rep. 2017 Dec 8;7(1):17220. doi: 10.1038/s41598-017-17376-0.

Hypoxia-inducible factor prolyl-4-hydroxylase-1 is a convergent point in the reciprocal negative regulation of NF-κB and p53 signaling pathways.

Author information

1
Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, FIN-90014, Finland.
2
Biocenter Oulu, University of Oulu, Oulu, FIN-90014, Finland.
3
Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, FIN-90014, Finland.
4
Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, FIN-90014, Finland. johanna.myllyharju@oulu.fi.
5
Biocenter Oulu, University of Oulu, Oulu, FIN-90014, Finland. johanna.myllyharju@oulu.fi.
6
Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, FIN-90014, Finland. johanna.myllyharju@oulu.fi.

Abstract

Hypoxia-inducible factor 1α (HIF1α) induces the expression of several hundred genes in hypoxia aiming at restoration of oxygen homeostasis. HIF prolyl-4-hydroxylases (HIF-P4Hs) regulate the stability of HIF1α in an oxygen-dependent manner. Hypoxia is a common feature in inflammation and cancer and the HIF pathway is closely linked with the inflammatory NF-κB and tumor suppressor p53 pathways. Here we show that genetic inactivation or chemical inhibition of HIF-P4H-1 leads to downregulation of proinflammatory genes, while proapoptotic genes are upregulated. HIF-P4H-1 inactivation reduces the inflammatory response under LPS stimulus in vitro and in an acute skin inflammation model in vivo. Furthermore, HIF-P4H-1 inactivation increases p53 activity and stability and hydroxylation of proline 142 in p53 has an important role in this regulation. Altogether, our data suggest that HIF-P4H-1 inhibition may be a promising therapeutic candidate for inflammatory diseases and cancer, enhancing the reciprocal negative regulation of the NF-κB and p53 pathways.

PMID:
29222481
PMCID:
PMC5722952
DOI:
10.1038/s41598-017-17376-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center