Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappaB.
dc.contributor.author | Nagarajan, R P | |
dc.contributor.author | Chen, F | |
dc.contributor.author | Li, W | |
dc.contributor.author | Vig, E | |
dc.contributor.author | Harrington, M A | |
dc.contributor.author | Nakshatri, H | |
dc.contributor.author | Chen, Y | |
dc.date.accessioned | 2019-04-16T20:37:09Z | |
dc.date.available | 2019-04-16T20:37:09Z | |
dc.date.issued | 2000-06-15 | |
dc.description | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1221102/ | en_US |
dc.description.abstract | Activation of transforming growth factor-beta (TGF-beta) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-beta and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor kappaB (NF-kappaB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-kappaB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IkappaB, an inhibitor of NF-kappaB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-kappaB binding site. This inhibitory effect appeared to be common to other TGF-beta- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-alpha was able to inhibit TGF-beta- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-kappaB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-kappaB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators. | en_US |
dc.identifier.citation | Nagarajan, R. P., Chen, F., Li, W., Vig, E., Harrington, M. A., Nakshatri, H., & Chen, Y. (2000). Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappaB. Biochemical Journal, 348(Pt 3), 591–596. | en_US |
dc.identifier.issn | 0264-6021 | |
dc.identifier.uri | https://hdl.handle.net/1805/18861 | |
dc.language.iso | en_US | en_US |
dc.publisher | Portland Press | en_US |
dc.subject | activin | en_US |
dc.subject | p300 | en_US |
dc.subject | signal transduction | en_US |
dc.subject | Smad7 | en_US |
dc.subject | transcription factor | en_US |
dc.title | Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappaB. | en_US |
dc.type | Article | en_US |