Prolyl hydroxylase-1 negatively regulates I [kappa]B kinase-[beta], giving insight into hypoxia-induced NF[kappa]B activity

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