{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:18:44Z","timestamp":1789525124772,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["105307\/Z\/14\/Z"],"award-info":[{"award-number":["105307\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C99667\/A12918"],"award-info":[{"award-number":["C99667\/A12918"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["KO1853\/1"],"award-info":[{"award-number":["KO1853\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>NF-\u03baB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-\u03baB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1\u03b1 modulates NF-\u03baB transcriptional response, very little is understood regarding how HIF-1\u03b2 contributes to NF-\u03baB signalling. Here, we demonstrate that HIF-1\u03b2 is required for full NF-\u03baB activation in cells following canonical and non-canonical stimuli. We found that HIF-1\u03b2 specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1\u03b2 binds to the TRAF6 gene and controls its expression independently of HIF-1\u03b1. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1\u03b2. These results indicate that HIF-1\u03b2 is an important regulator of NF-\u03baB with consequences for homeostasis and human disease.<\/jats:p>","DOI":"10.3390\/ijms21083000","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T11:42:14Z","timestamp":1587728534000},"page":"3000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["HIF-1\u03b2 Positively Regulates NF-\u03baB Activity via Direct Control of TRAF6"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1707-4773","authenticated-orcid":false,"given":"Laura","family":"D\u2019Ignazio","sequence":"first","affiliation":[{"name":"Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK"},{"name":"The Lieber Institute for Brain Development,  Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilem","family":"Shakir","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7508-6641","authenticated-orcid":false,"given":"Michael","family":"Batie","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Arno","family":"Muller","sequence":"additional","affiliation":[{"name":"Developmental Genetics Unit, Institute of Biology, University of Kassel, 34132 Kassel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2413-4981","authenticated-orcid":false,"given":"Sonia","family":"Rocha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2016.12.012","article-title":"30 years of NF-kappab: A blossoming of relevance to human pathobiology","volume":"168","author":"Zhang","year":"2017","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm2083","article-title":"Integrating cell-signalling pathways with NF-kappab and IKK function","volume":"8","author":"Perkins","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.3389\/fimmu.2018.01849","article-title":"Tumor necrosis factor receptor-associated factor regulation of nuclear factor kappab and mitogen-activated protein kinase pathways","volume":"9","author":"Shi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"859","DOI":"10.3892\/ijmm.2015.2079","article-title":"The role of hypoxia in inflammatory disease (Review)","volume":"35","author":"Biddlestone","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"D\u2019Ignazio, L., Batie, M., and Rocha, S. (2017). Hypoxia and inflammation in cancer, focus on HIF and NF-kappab. Biomedicines, 5.","DOI":"10.20944\/preprints201703.0240.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.tibs.2007.06.005","article-title":"Gene regulation under low oxygen: Holding your breath for transcription","volume":"32","author":"Rocha","year":"2007","journal-title":"Trends Biochem. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cardiores.2006.05.005","article-title":"Regulating cellular oxygen sensing by hydroxylation","volume":"71","author":"Fandrey","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/nri.2017.103","article-title":"Regulation of immunity and inflammation by hypoxia in immunological niches","volume":"17","author":"Taylor","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1042\/BJ20051839","article-title":"Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44\/42 mapk and nf-kappab","volume":"396","author":"Frede","year":"2006","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1161\/01.ATV.0000258979.92828.bc","article-title":"Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappab site","volume":"27","author":"Bonello","year":"2007","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1042\/BJ20080476","article-title":"Regulation of hypoxia-inducible factor-1alpha by NF-kappab","volume":"412","author":"Kenneth","year":"2008","journal-title":"Biochem. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Van Uden, P., Kenneth, N.S., Webster, R., Muller, H.A., Mudie, S., and Rocha, S. (2011). Evolutionary conserved regulation of HIF-1beta by NF-kappab. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1001285"},{"key":"ref_13","first-page":"169","article-title":"HIF-1alpha restricts NF-kappab-dependent gene expression to control innate immunity signals","volume":"8","author":"Bandarra","year":"2015","journal-title":"Dis. Models Mech."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"D\u2019Ignazio, L., Batie, M., and Rocha, S. (2018). Tnfsf14\/light, a non-canonical NF-kappab stimulus, induces the HIF pathway. Cells, 7.","DOI":"10.20944\/preprints201807.0007.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1126\/science.1162818","article-title":"The aryl hydrocarbon nuclear translocator alters CD30-mediated NF-kappab-dependent transcription","volume":"323","author":"Wright","year":"2009","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.molcel.2012.09.028","article-title":"EGFR-induced and pkcepsilon monoubiquitylation-dependent NF-kappab activation upregulates pkm2 expression and promotes tumorigenesis","volume":"48","author":"Yang","year":"2012","journal-title":"Mol. Cell."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Strowitzki, M.J., Cummins, E.P., and Taylor, C.T. (2019). Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: Unique or ubiquitous?. Cells, 8.","DOI":"10.3390\/cells8050384"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.biocel.2011.08.003","article-title":"The emerging role of nuclear factor kappa b in renal cell carcinoma","volume":"43","author":"Morais","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1006\/dbio.1997.8758","article-title":"Arnt-deficient mice and placental differentiation","volume":"191","author":"Kozak","year":"1997","journal-title":"Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4713","DOI":"10.1128\/MCB.23.13.4713-4727.2003","article-title":"P53 represses cyclin d1 transcription through down regulation of bcl-3 and inducing increased association of the p52 NF-kappab subunit with histone deacetylase 1","volume":"23","author":"Rocha","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4820","DOI":"10.1038\/sj.emboj.7601343","article-title":"Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappab subunit","volume":"25","author":"Schumm","year":"2006","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrc3204","article-title":"The diverse and complex roles of NF-kappab subunits in cancer","volume":"12","author":"Perkins","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.molmed.2017.11.002","article-title":"Checkpoints in TNF-induced cell death: Implications in inflammation and cancer","volume":"24","author":"Annibaldi","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"a000232","DOI":"10.1101\/cshperspect.a000232","article-title":"NF-kappab in the immune response of drosophila","volume":"1","author":"Hetru","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s10495-018-1490-7","article-title":"Tak1 mediates convergence of cellular signals for death and survival","volume":"24","author":"Aashaq","year":"2019","journal-title":"Apoptosis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.15252\/embj.201591437","article-title":"Egln2 associates with the nrf1-pgc1alpha complex and controls mitochondrial function in breast cancer","volume":"34","author":"Zhang","year":"2015","journal-title":"EMBO J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.sbi.2016.09.011","article-title":"Structural characterization of mammalian BHLH-pas transcription factors","volume":"43","author":"Wu","year":"2017","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/imr.12302","article-title":"Tumor necrosis factor receptor-associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system","volume":"266","author":"Walsh","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/cdd.2017.17","article-title":"The role of hybrid ubiquitin chains in the MYD88 and other innate immune signalling pathways","volume":"24","author":"Cohen","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1046\/j.1365-2443.1999.00265.x","article-title":"Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in traf6-deficient mice","volume":"4","author":"Naito","year":"1999","journal-title":"Genes Cells"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.celrep.2018.01.013","article-title":"Traf6 mediates basal activation of NF-kappab necessary for hematopoietic stem cell homeostasis","volume":"22","author":"Fang","year":"2018","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e121175","DOI":"10.1172\/jci.insight.121175","article-title":"Epithelial traf6 drives IL-17-mediated psoriatic inflammation","volume":"3","author":"Matsumoto","year":"2018","journal-title":"JCI Insight"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1084\/jem.20160659","article-title":"Development of intestinal m cells and follicle-associated epithelium is regulated by traf6-mediated NF-kappab signaling","volume":"215","author":"Kanaya","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1620\/tjem.236.139","article-title":"TNF receptor-associated factor (TRAF) signaling network in CD4(+) T-lymphocytes","volume":"236","author":"So","year":"2015","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1111\/jcmm.13439","article-title":"Traf6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma","volume":"22","author":"Chen","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/ncb3445","article-title":"A hypoxia-responsive traf6-atm-h2ax signalling axis promotes HIF1alpha activation, tumorigenesis and metastasis","volume":"19","author":"Rezaeian","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.3389\/fimmu.2018.02096","article-title":"Activation of RIG-I-mediated antiviral signaling triggers autophagy through the mavs-traf6-beclin-1 signaling axis","volume":"9","author":"Lee","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13046-017-0502-8","article-title":"Cinchonine induces apoptosis of Hela and A549 cells through targeting traf6","volume":"36","author":"Qi","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.biocel.2014.04.010","article-title":"Traf6 is upregulated in colon cancer and promotes proliferation of colon cancer cells","volume":"53","author":"Sun","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"eaah6275","DOI":"10.1126\/scisignal.aah6275","article-title":"Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in transcriptomine","volume":"10","author":"Becnel","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/s41597-019-0193-4","article-title":"The signaling pathways project, an integrated \u2018omics knowledgebase for mammalian cellular signaling pathways","volume":"6","author":"Ochsner","year":"2019","journal-title":"Sci. Data"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D726","DOI":"10.1093\/nar\/gkv1160","article-title":"Encode data at the encode portal","volume":"44","author":"Sloan","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Consortium","year":"2012","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"Gepia2: An enhanced web server for large-scale expression profiling and interactive analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8596","DOI":"10.1073\/pnas.141235698","article-title":"Physical and functional interactions between drosophila TRAF2 and pelle kinase contribute to dorsal activation","volume":"98","author":"Shen","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.devcel.2013.10.017","article-title":"Atg9 interacts with dtraf2\/traf6 to regulate oxidative stress-induced JNK activation and autophagy induction","volume":"27","author":"Tang","year":"2013","journal-title":"Dev. Cell."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1016\/j.cellsig.2014.09.016","article-title":"Traf6 is a novel regulator of notch signaling in drosophila melanogaster","volume":"26","author":"Mishra","year":"2014","journal-title":"Cell Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9108","DOI":"10.1074\/jbc.274.13.9108","article-title":"Nuclear retention of ikappabalpha protects it from signal-induced degradation and inhibits nuclear factor kappab transcriptional activation","volume":"274","author":"Rodriguez","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1042\/BJ20120625","article-title":"Tfr1 interacts with the IKK complex and is involved in IKK-NF-kappab signalling","volume":"449","author":"Kenneth","year":"2013","journal-title":"Biochem. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/978-1-4939-3578-9_16","article-title":"Visualizing genomic data using gviz and bioconductor","volume":"1418","author":"Hahne","year":"2016","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/3000\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:27:08Z","timestamp":1760365628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/3000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,24]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21083000"],"URL":"https:\/\/doi.org\/10.3390\/ijms21083000","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202003.0168.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,24]]}}}