Molecular mechanisms of regulation of type I collagen biosynthesis

摘要

Type I collagen is a heterotrimeric protein composed of two α(I) and one α2(I) polypeptide chains, each encoded by a unique gene. Both collagen genes are coordinately regulated in response to a variety of endogenous and exogenous stimuli. Collagen genes are mainly regulated by transcriptional mechanisms, although post- transcriptional regulatory mechanisms have occasionally been documented. To understand the molecular basis of transcriptional control, we have been studying the cis-regulatory sequence motifs of human pro αl(I) collagen gene and trans-acting factors with which these elements interact. The major elements include TATA and CCAAT boxes, Ap-l , Ap-2, NF-I and Spl , and a unique TGF beta l -activating element. Transcription factor Spl is obligatory for the activation of the Pro αl(I) promoter since it failed to be activated in Drosophila SL2 cells that lack Spl. Of the six putative Spl motifs in the Pro αl(I) collagen promoter and the first intron, the most proximal Spl element located at -87`to -82 bp was sufficient for its Spl -dependent activation. Additional cis-acting motifs in the intron of the Pro αl (I) gene, including an Ap-l site, participated in its regulation by TGF beta l and okadaic acid. Thus, activation of Pro α 1(I) promoter involves combinatorial actions of multiple ubiquitous and unique cis-regulatory elements. -