Transcriptional regulation of type I collagen gene expression by transforming growth factor-β and Smad proteins

Increased production of type I collagen is a common hallmark of fibrotic diseases in various organs including the liver. This increase is exerted mainly at the level of transcription, and transforming growth factor-beta (TGF beta) is the key factor in stimulating gene transcription. We have previously shown that the -313 to -183 upstream sequence of alpha2(I) collagen gene (COL1A2) is essential for basal and TGF beta -stimulated transcription in skin fibroblasts and hepatic stellate cells. We designated this region the TGF beta -responsive element (TbRE) and revealed that a ubiquitous trans-activator Sp1 and unknown nuclear factor(s) bind to this region to mediate the stimulatory effect of TGF beta. Experiments using transgenic mice harboring the -313 COL1A2 promoter have revealed that the promoter is activated in a cell type-specific manner during hepatic fibrogenesis in vivo. Smad proteins have been recently identified as mediators of intracellular signal transduction of TGF beta superfamily members. One of them, Smad3 is shown to bind to the TbRE and is implicated in mediating TGF beta -elicited stimulation of COL1A2 transcription.