Molecular mechanisms of regulation of type I collagen biosynthesis

Type I collagen is a heterotrimeric protein composed of two alpha 1(I) and one alpha 2(I) polypeptide chains, each encoded by a unique gene. Both coll agen genes are coordinately regulated in response to a variety of endogenou s and exogenous stimuli. Collagen genes are mainly regulated by transcripti onal mechanisms, although posttranscriptional regulatory mechanisms have oc casionally been documented. To understand the molecular basis of transcript ional control, we have been studying the cis-regulatory sequence motifs of human Pro alpha 1(I) collagen gene and trans-acting factors with which thes e elements interact. The major elements include TATA and CCAAT boxes, Ap-l, Ap-2, NF-I and Spl, and a unique TGF beta 1-activating element. Transcript ion factor Spl is obligatory for the activation of the Pro alpha 1(I) promo ter since it failed to be activated in Drosophila SL2 cells that lack Spl. Of the six putative Spl motifs in the Pro alpha 1(I) collagen promoter and the first intron, the most proximal Spl element located at -87 to -82 bp wa s sufficient for its Spl-dependent activation. Additional cis-acting motifs in the intron of the Pro alpha 1(I) gene, including an Ap-1 site, particip ated in its regulation by TGF beta 1 and okadaic acid. Thus, activation of Pro alpha 1(I) promoter involves combinatorial actions of multiple ubiquito us and unique cis-regulatory elements.