Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proceedings of the National Academy of Sciences of the United States of America

Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2006; 103(48):18154-9. DOI: 10.1073/pnas.0602235103
Source: PubMed


Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFkappaB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFkappaB through a pathway involving activation of IkappaB kinase-beta (IKKbeta) leading to phosphorylation-dependent degradation of IkappaBalpha and liberation of NFkappaB. Furthermore, through increasing the pool and/or activation potential of IKKbeta, hypoxia amplifies cellular sensitivity to stimulation with TNFalpha. Within its activation loop, IKKbeta 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 NFkappaB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFkappaB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFkappaB. Hypoxia increases both the expression and activity of IKKbeta, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKbeta hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFkappaB activity through decreased PHD-dependent hydroxylation of IKKbeta, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways.

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    • "Indeed, the relationship between the hypoxic and inflammatory responses is tightly controlled (Figure 2A). As noted above, hypoxia and bacterial infections result in increased nuclear factor-kappa B (NF-kB) activity in phagocytes, which in turn induces HIF-1a mRNA transcription (Cummins et al., 2006; Fitzpatrick et al., 2011; Rius et al., 2008). Together with NF-kB, the p42/ p44 mitogen-activated protein kinase (MAPK) (Erk) pathway is involved in LPS-induced HIF-1a induction in human monocytes (Frede et al., 2006). "
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    • "Under normal conditions, HIF activity is rendered inactive by prolyl hydroxylases (PHD) and factor inhibiting HIF (FIH). Both PHD and FIH prevent the activation of IκB kinase B and hence inhibit NF-κB activation [23–27]. "
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    • "There is a tight interconnection between the NFκB and HIF-1α (hypoxia-inducible factor 1-α) signaling pathways in the regulation of inflammatory host responses (Barnes, 1997; Taylor, 2008). Thus, NFκB is activated under hypoxia (Cummins et al., 2006) but in turn also induces transcriptional up-regulation of HIF-1α expression (Rius et al., 2008). NFκB activation and subsequent pro-inflammatory gene expression is supposed to be abrogated by an enhanced expression of IκB kinase-α (IKKα) under prolonged hypoxia (Lawrence et al., 2005; Cummins et al., 2006). "
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