title: Further insights into the mechanism of hypoxia-induced NFκB. [corrected].
abstract: The cellular response to hypoxia relies on the activation of a specific transcriptional program. Although, most of the attention is focused on the transcription factor HIF, other transcription factors are also activated in hypoxia. We have recently described the mechanism for hypoxia induced NFκB. We have demonstrated the crucial dependency on the IKK complex as well as in the upstream IKK kinase TAK1. TAK1 and IKK activation is dependent upon the calcium calmodulin kinase, CaMK2 and requires Ubc13 as the E2 ubiquitin conjugation enzyme. We report a role for XIAP as the possible E3-ubiquitin ligase for this system. Interestingly, hypoxia induced IKK mediated phosphorylation of IκBα, does not lead to degradation. Hypoxia prevents IκBα de-sumoylation of Sumo-2/3 chains on critical lysine residues, normally required for K-48 linked polyubiquitination. Our results define a novel pathway regulating NFκB activation.
authors.affiliation: College of Life Sciences, Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee, Scotland, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Melvin
authors.forename: Sharon
authors.initials: S
authors.lastname: Mudie
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099151:MAP Kinase Kinase Kinase 7