A NEW CIS-ACTING ELEMENT INVOLVED IN TISSUE-SELECTIVE GLUCOCORTICOID INDUCIBILITY OF TYROSINE AMINOTRANSFERASE GENE-EXPRESSION

Tyrosine aminotransferase (TAT), a prototypical steroid hormone-inducible gene, has been used extensively in studies of tissue-specific control of gene transcription. Over the last several years, a total of five cis-acting elements have been implicated in the tissue-specific expression and induction of the TAT gene in rat liver. These elements are all located upstream of the start of transcription, at -11, -5.5, -3.6, -2.5, and approximately -0.1 kilobases (kb). We now have used both stable and transient transfection assays to define a new element between -2.56 and -2.3 kb that regulates the fold induction by glucocorticoids in a tissue-selective manner. Compared to simple glucocorticoid-regulated constructs, which were used as controls, the major effect of this element was repression of glucocorticoid inducibility in nonliver cells. This activity was both orientation and position independent and was seen with homologous and heterologous promoters and genes. Although this element, therefore, possessed silencer-like activity, it was unable to extinguish gene expression in nonliver cells. In fact, the observance of some glucocorticoid-induced gene expression was additional evidence that the repression derived from an element that is distinct from the glucocorticoid-responsive element at -2.5 kb. A second element was found between -2.95 and -2.56 kb that acts in a tissue nonspecific manner to reduce the absolute level of gene expression in both hepatic and nonhepatic cells. The combined effects of this tissue-nonselective element and the above-mentioned tissue-selective element were to almost completely eliminate glucocorticoid inducibility in non-hepatic cells.