Transforming Growth Factor-beta 1 Up-Regulation of Human alpha(1)(I) Collagen Is Mediated by Sp1 and Smad2 Transacting Factors

Hepatic fibrosis results from excessive deposition of type I collagen. The roles of Smads in mediating the effect of transforming growth factor-beta 1 (TGF beta 1) on activation of the alpha(1)(I) collagen promoter were determined. Smads bind in association with Sp1 to the CC(GG)-rich TGF beta 1 responsive element of the promoter that lacks the classical Smad recognition element, and enhance binding of Sp1. In transfection experiments, TGF beta 1 activated a proximal promoter, but not promoters mutated at sites that prevented Sp1 binding. Sp1 alone or the combination of Smad2 and Smad4 activated the promoter in transfected human LX-2 stellate cells. Sp1 or Smad2 knockdowns with siRNAs prevented the effect of TGF beta 1 in enhancing the promoter. In conclusion, this study shows that Smads bind in association with Sp1 to the CC(GG)-rich TGF beta 1 responsive element of the human alpha(1)(I) collagen promoter that lacks the classical Smad recognition element, thus enhancing the binding of Sp1 and in this manner activating the collagen promoter.