A single regulatory module of the carbamoylphosphate synthetase I gene executes its hepatic program of expression

A 469-base pair (bp) upstream regulatory fragment (URF) and the proximal pr omoter of the carbamoylphosphate synthetase I (CPS) gene were analyzed for their role in the regulation of spatial, developmental, and hormone-induced expression in vivo. The URF is essential and sufficient for hepatocyte-spe cific expression, periportal localization, perinatal activation and inducti on by glucocorticoids, and cAMP in transgenic mice. Before birth, the trans gene is silent but can be induced by cAMP and glucocorticoids, indicating t hat these compounds are responsible for the activation of expression at bir th. A 102-bp glucocorticoid response unit within the URF, containing bindin g sites for HNF3, C/EBP, and the glucocorticoid receptor, is the main deter minant of the hepatocyte-specific and hormone-controlled activity. Addition al sequences are required for a productive interaction between this minimal response unit and the core CPS promoter. These results show that the 469-b p URF, and probably only the 102-bp glucocorticoid response unit, functions as a regulatory module, in that it autonomously executes a correct spatial , developmental and hormonal program of CPS expression in the liver.