Cummins, E.P. and Berra, E. and Comerford, K.M. and Ginouves, A. and Fitzgerald, K.T. and Seeballuck, F. and Godson, C. and Nielsen, J.E. and Moynagh, Paul N. and Pouyssegur, J. and Taylor, C.T. (2006) Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. Proceedings of the National Academy of Sciences, 103 (48). pp. 18154-18159. ISSN 1091-6490

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Abstract

Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFκB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFκB through a pathway involving activation of IκB kinase-β (IKKβ) leading to phosphorylation-dependent degradation of IκBα and liberation of NFκB. Furthermore, through increasing the pool and/or activation potential of IKKβ, hypoxia amplifies cellular sensitivity to stimulation with TNFα. Within its activation loop, IKKβ contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NFκB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFκB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFκB. Hypoxia increases both the expression and activity of IKKβ, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKβ hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFκB activity through decreased PHD-dependent hydroxylation of IKKβ, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways.

Item Type:	Article
Additional Information:	We thank Anne Marie Griffin for expert technical assistance. pEGLN2 plasmids were a kind gift from Dr. William Kaelin (Harvard Medical School, Boston, MA). This work was supported by grants from Science Foundation Ireland, the Health Research Board of Ireland, the Wellcome Trust, the Government of Ireland Programme for Research in Third Level Institutions, Centre National de la Recherche Scientifique, and La Ligue Nationale Contre le Cancer
Keywords:	IKK; Prolyl hydroxylase-1; IκB kinase-β; hypoxia-induced NFκB activity;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	7204
Identification Number:	https://doi.org/10.1073/pnas.0602235103
Depositing User:	Professor Paul Moynagh
Date Deposited:	20 Jul 2016 10:01
Journal or Publication Title:	Proceedings of the National Academy of Sciences
Publisher:	National Academy of Sciences
Refereed:	Yes
Funders:	Science Foundation Ireland (SFI), Health Research Board (HRB), Wellcome Trust, Programme for Research in Third Level Institutions, Centre National de la Recherche Scientifique, La Ligue Nationale Contre le Cancer
URI:	http://www.pnas.org
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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