Binding of the heterotrimer composed of SMAD4 and two molecules of phosphorylated SMAD3 the promoter of the collagen I gene COL1A2, together with the transcription factor SP1 (Zhang et al. 2000, Ihn et al. 2006) and the histone acetyltransferase EP300 (p300) (Higashi, Inagaki, Suzuki et al. 2003, Higashi, Inagaki, Fujimori et al. 2003, Ihn et al. 2006), stimulates COL1A2 gene transcription. SMAD2 interferes with SMAD3-stimulated COL1A2 gene expression (Meng et al. 2010). Binding of the transcription factor YBX1, activated by interferon-gamma (IFNG) signaling, to SMAD3 at the COL1A2 promoter inhibits COL1A2 transcription (Higashi, Inagaki, Suzuki et al. 2003; Higashi, Inagaki, Fujimori et al. 2003). SMAD3-mediated upregulation of COL1A2 promotes tissue fibrosis, including pulmonary and renal fibrosis. SMAD2 has a protective effect against renal fibrosis (Meng et al. 2010). The inhibitory action of YBX1 is thought to be responsible for the anti-fibrotic effect of IFNG signaling (Dooley et al. 2006).