Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB

Raman P. Nagarajan, Feifei Chen, Wei Li, Eva Vig, Maureen A. Harrington, Harikrishna Nakshatri, Yan Chen

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Activation of transforming growth factor-β (TGF-β) 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-β 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 κB (NF-κB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-κB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IκB, an inhibitor of NF-κB. 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-κB binding site. This inhibitory effect appeared to be common to other TGF-β- 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-κB by tumour necrosis factor-α (TNF-α) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-α was able to inhibit TGF-β- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription coactivator p300 could abrogate the inhibitory effect of NF-κB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-κB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.

Original languageEnglish (US)
Pages (from-to)591-596
Number of pages6
JournalBiochemical Journal
Volume348
Issue number3
DOIs
StatePublished - Jun 15 2000

Keywords

  • Activin
  • p300
  • Signal transduction
  • Smad7
  • Transcription factor

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB'. Together they form a unique fingerprint.

  • Cite this