CHARACTERIZATION OF TGF-BETA PROMOTERS

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Five different isoforms of TGF-Beta have now been described. Three of these, called TGF-Betas 1, 2, and 3, are expressed in mammalian cells. The significance of three distinct genes encoding proteins of overlapping activity might lie in the differential expression of each gene under different physiological conditions. There is already substantial evidence of differential control of TGF-Beta gene expression both in vitro and in vivo. The purpose of this project is to gain insight into the molecular mechanisms of transcriptional control of TGF-Beta expression in mammalian cells by cloning and subsequent analysis of the promoter regions of the genes for TGF-Betas 1, 2, and 3. The promoter sequences regulating expression of,TGF-Beta1 have been demonstrated to contain AP-1 sites which bind the Jun/Fos dimer. By assessment of the activity of transfected chimeric constructs of these regions of the TGF-Beta1 promoter linked to the bacterial gene encoding chloramphenicol acetyltransferase, these AP-1 sites have been directly implicated in regulation of TGF-Beta expression by TGF-Beta itself, by phorbol ester, and by the Tax transactivating protein of the human retrovirus HTLV-I. Recently, we have also cloned and completed a preliminary characterization of the 5' flanking regions of the human TGF-B2 and TGF-B3 genes. The regulatory regions of the TGF-B2 and 3 genes differ significantly from that of the TGF-Beta1 gene in that they each contain TATAA boxes immediately upstream of the transcriptional start sites and each contain CRE or cyclic AMP response elements which appear to mediate transcriptional activation of these genes by forskolin. Present studies are aimed at correlating these effects on