NF-κB suppresses HIF-1α response by competing for P300 binding

Dec 29, 2010Biochemical and biophysical research communications

NF-κB reduces HIF-1α activity by competing for a shared helper protein

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Abstract

Inflammatory stimulation (TNF-α treatment) causes a marked inhibition of HIF-1α function at the HRE in all cell lines studied.

HIF-1α mediates responses to hypoxia, including bone induction through VEGF.
NF-κB signaling is associated with the inhibition of bone repair in inflammatory conditions.
Co-transfection with p65 reduces transcription of hVEGFp following hypoxia induced by DFO.
TNF-α treatment does not significantly alter HIF-1α mRNA levels.
The interaction between HIF-1α and NF-κB is suggested to involve competition for a co-activator, p300, at gene promoters.

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Hypoxia has emerged as a key determinant of osteogenesis. HIF-1α is the transcription factor mediating hypoxia responses that include induction of VEGF and related bone induction. Inflammatory signals antagonize bone repair via the NF-κB pathway. The present investigation explored the functional relationship of hypoxia (HIF-1α function) and inflammatory signaling (NF-κB) in stem like and osteoprogenitor cell lines. The potential interaction between HIF-1α and NF-κB signaling was explored by co-transfection studies in hFOB with p65, HIF-1α and 9x-HRE-luc or HIF-1α 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-α treatment) causes a marked inhibition of HIF-1α 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-α treatment had little effect on HIF-1α mRNA levels. The functional interaction of Gal4-HIF-1α and VP16-p300 fusion proteins is effectively blocked by expression of p65 in a dose dependent manner. It was concluded that NF-κB-mediated inflammatory signaling is able to block HIF-1α 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.

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NF-κB suppresses HIF-1α response by competing for P300 binding

Abstract

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