Type 1 collagen is a major structural protein which is abundantly expressed in bones, tendons and skin and is present in lower concentrations in connective tissues of other organs. The genes for the two chains of type I collagen are coordinately expressed during embryonic development and also in most physiological and pathological situations in adult animals. The expression of these genes is likely to be the result of complex combinatorial control mechanisms involving both tissue-specific and ubiquitous transcription factors. The exaggerated synthesis of type I collagen in a number of fibrotic diseases, probably results from the abnormal activation of some of these transcription factors. Our laboratory has focused its efforts on a ubiquitous transcription factor, CBF, which is an important physiological activator of both the alpha1(I) and alpha2(I) collagen genes. CBF binds to a CCAAT motif in each promoter within 100 bp upstream of the start of transcription, as a heteromeric protein which needs three different subunits, CBF-A, CBF-B and CBF-C to bind to DNA. CBF-A forms a tight complex with CBF-C and this complex binds to CBF-B; the complex of three different polypeptides then interacts with DNA. Based on the hypothesis that CBF is a key transcriptional activator of the two type I collagen genes, the experimental approach outlined in this application focuses on an extensive molecular characterization of this protein in order to better understand the mechanisms whereby CBF activates these genes. These studies will examine how the subunits of CBF interact with each other, how they interact with a specific DNA sequence, and how they interact with other transcription factors in order to activate the type I collagen promoters. We believe that these studies will constitute an important step in the elucidation of the complex transcription controls of the type I collagen genes.
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