SRF is a nuclear repressor of Smad3-mediated TGF-beta signaling

Serum response factor (SRF) is a widely expressed transcription factor involved in immediate-early and tissue-specific gene expression, cell proliferation and differentiation. We defined a new role of SRF as a nuclear repressor of the tumor growth factor beta 1 (TGF-beta 1) growth-inhibitory signal during cell proliferation. We show that SRF significantly inhibits the TGF-beta 1/Smad-dependent transcription by associating with Smad3. SRF causes resistance to the TGF-beta 1 cytostatic response by directly repressing the Smad transcriptional activity and Smad binding to DNA. Furthermore, we demonstrated that overexpression of SRF markedly decreases the level of Smad3 complex binding to the promoters of Smad3 target genes, p15(INK4b) and p21(Cip1). This leads to the inhibition of expression of TGF-beta 1-responsive genes. SRF therefore acts as a nuclear repressor of Smad3-mediated TGF-beta 1 signaling.