Evolutionary conservation of the five different TGF-Beta genes currently known to be expressed in vertebrate cells suggests that these TGF-Betas have specific functions in normal development. In order to investigate the overall control of TGF-Beta gene expression, we have characterized the promoter regions of TGF-Beta 1, Beta 2 and Beta 3. The 5' flanking regions of the three genes are distinctly different. We have shown that the AP-1 binding sites in the TGF-Beta 1 promoter are the targets of activation of TGF-Beta 1 promoter activity by the human T lymphotropic virus type 1 (HTLV-1). Experiments with transgenic mice carrying the HTLV-1 tax gene confirm these results and demonstrate that tissues expressing high levels of the tax gene also express elevated levels of TGF-Beta 1 mRNA. Recently, it has been found that cAMP induces expression of TGF-Beta 2 and TGF-Beta 3 in a cell-type specific manner. Recent studies demonstrate that the products of the tumor suppressor gene, Rb, activates expression of the TGF-Beta 1 promoter through an Sp1 binding site and of the TGF-Beta 2 promoter through an ATF-2 binding site. These results have important implications for the mechanism of action of Rb in suppression of cell growth, suggesting that its actions, in part, are mediated by secretion of a negative regulator of growth. Besides transcriptional control, there are numerous reports suggesting that expression of TGF-Beta isoforms may also be regulated post-transcriptiona- lly. We have shown that the 5' untranslated region exerts a potent inhibitory effect on the expression of a heterologous reporter gene, suggesting a role for the 5' untranslated region in the post-transc- riptional regulation of TGF-Beta 1.
