Rp. Nagarajan et al., Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappa B, BIOCHEM J, 348, 2000, pp. 591-596
Activation of transforming growth factor-beta (TGF-beta) and activin recept
ors 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 activi
n signalling in a negative-feedback loop, mediated by a direct regulation b
y Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. I
nterestingly, we found that the Smad7 promoter was also regulated by nuclea
r factor kappa B (NF-kappa B), a transcription factor which plays an import
ant role in inflammation and the immune response, Expression of NF-kappa B
p65 subunit was able to inhibit the Smad7 promoter activity, and this inhib
ition could be reversed by co-expression of I kappa B, an inhibitor of NF-k
appa B. In addition, the inhibitory activity of p65 was observed in a minim
al promoter that contained only the Smad7 SEE and a TATA box, without any c
onsensus NF-kappa B binding site. This inhibitory effect appeared to be com
mon to other TGF -beta- and activin-responsive promoters, since p65 also in
hibited the forkhead-activin-signal-transducer-2-med activation of a Xenopu
s Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which
contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 p
romoter. Activation of endogenous NF-kappa B by tumour necrosis factor-alph
a (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryoni
c kidney 293 cells. In human hepatoma HepG2 cells, TNF-alpha was able to in
hibit TGF-beta- and activin-mediated transcriptional activation. Furthermor
e, overexpression of the transcription coactivator p300 could abrogate the
inhibitory effect of NF-kappa B on the Smad7 promoter. Taken together, thes
e data have indicated a novel mode of crosstalk between the Smad and the NF
-kappa B signalling cascades at the transcriptional level by competing for
a limiting pool of transcription co-activators.