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pubmed-article:21187066pubmed:abstractTextHypoxia has emerged as a key determinant of osteogenesis. HIF-1? is the transcription factor mediating hypoxia responses that include induction of VEGF and related bone induction. Inflammatory signals antagonize bone repair via the NF-?B pathway. The present investigation explored the functional relationship of hypoxia (HIF-1? function) and inflammatory signaling (NF-?B) in stem like and osteoprogenitor cell lines. The potential interaction between HIF-1? and NF-?B signaling was explored by co-transfection studies in hFOB with p65, HIF-1? and 9x-HRE-luc or HIF-1? target genes reporter plasmids. Nuclear cross-talk was directly tested using the mammalian Gal4/VP16 two-hybrid, and confirmed by co-immunoprecipitation/western blotting assays. The results show that inflammatory stimulation (TNF-? treatment) causes a marked inhibition of HIF-1? function at the HRE in all cell lines studied. Also, co-transfection with p65 expression vector leads to reduced hVEGFp transcription after DFO-induced hypoxia. However, TNF-? treatment had little effect on HIF-1? mRNA levels. The functional interaction of Gal4-HIF-1? and VP16-p300 fusion proteins is effectively blocked by expression of p65 in a dose dependent manner. It was concluded that NF-?B-mediated inflammatory signaling is able to block HIF-1? transactivation at HRE-encoding genes by direct competition for p300 binding at the promoter. Inflammation may influence the stem cell niche and tissue regeneration by influencing cellular responses to hypoxia.lld:pubmed
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pubmed-article:21187066pubmed:authorpubmed-author:CooperLyndon...lld:pubmed
pubmed-article:21187066pubmed:authorpubmed-author:MendonçaGusta...lld:pubmed
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pubmed-article:21187066pubmed:copyrightInfoCopyright © 2010 Elsevier Inc. All rights reserved.lld:pubmed
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pubmed-article:21187066pubmed:dateRevised2011-10-27lld:pubmed
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pubmed-article:21187066pubmed:articleTitleNF-?B suppresses HIF-1? response by competing for P300 binding.lld:pubmed
pubmed-article:21187066pubmed:affiliationUniversidade Católica de Brasília, Pós-Graduação em Ciências Genômicas e Biotecnologia, SGAN Quadra 916, Av. W5 Norte, 70790-160 Brasília, DF, Brazil.lld:pubmed
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