Ullah, K., Rosendahl, A., Izzi, V., Bergmann, U., Pihlajaniemi, T., Mäki, J., Myllyharju, J. (2017) Hypoxia-inducible factor prolyl-4-hydroxylase-1 is a convergent point in the reciprocal negative regulation of NF-κB and p53 signaling pathways. Scientific Reports, 7 (1), 17220. https://doi.org/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:||Ullah, Karim1,2,3; Rosendahl, Ann-Helen1,2,3; Izzi, Valerio1,2,3;|
1Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, FIN-90014, Finland
2Biocenter Oulu, University of Oulu, Oulu, FIN-90014, Finland
3Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, FIN-90014, Finland
|Online Access:||PDF Full Text (PDF, 7.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201901111971
|Publish Date:|| 2019-01-11
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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This study was supported by the Academy of Finland Center of Excellence 2012–2017 Grant 251314 (JM and TP), Academy of Finland Project Grant 296498, the S. Jusélius Foundation, the Jane and Aatos Erkko Foundation and FibroGen, Inc.
|Academy of Finland Grant Number:||
251314 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
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