COL1A2 gene expression is stimulated by p-2S-SMAD3:p-2S-SMAD3:SMAD4

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Reaction [omitted]
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
11007770 Synergistic cooperation between Sp1 and Smad3/Smad4 mediates transforming growth factor beta1 stimulation of alpha 2(I)-collagen (COL1A2) transcription

Greenwel, P, Ou, J, Ramirez, F, Inagaki, Y, Zhang, W

J Biol Chem 2000
12917425 Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction of YB-1 with Smad3

Higashi, K, Nakao, A, Nakatsuka, I, Kaneko, H, Inagaki, Y, Fujimori, K

J Biol Chem 2003
16319104 Constitutively phosphorylated Smad3 interacts with Sp1 and p300 in scleroderma fibroblasts

Tamaki, K, Yamane, K, Jinnin, M, Asano, Y, Ihn, H

Rheumatology (Oxford) 2006
12446674 Y-box-binding protein YB-1 mediates transcriptional repression of human alpha 2(I) collagen gene expression by interferon-gamma

Mitsui, S, Higashi, K, Mauviel, A, Suzuki, N, Nakatsuka, I, Kaneko, H, Inagaki, Y

J Biol Chem 2003
16278212 Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects

Gressner, AM, En-Nia, A, Floege, J, Said, HM, Mertens, PR, Dooley, S

J Biol Chem 2006
20595680 Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis

Chung, AC, Huang, XR, Lan, HY, Shao, X, Ju, W, Qin, W, Bottinger, EP, Igarashi, P, Meng, XM

J Am Soc Nephrol 2010
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