Hypoxia-inducible factor prolyl-4-hydroxylase-1 is a convergent point in the reciprocal negative regulation of NF-κB and p53 signaling pathways
Ullah, Karim; Rosendahl, Ann-Helen; Izzi, Valerio; Bergmann, Ulrich; Pihlajaniemi, Taina; Mäki, Joni M.; Myllyharju, Johanna (2017-12-08)
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
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https://urn.fi/URN:NBN:fi-fe201901111971
Tiivistelmä
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.
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