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J. Biol. Chem., Vol. 275, Issue 51, 40020-40027, December 22, 2000
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From the A 469-base pair (bp) upstream regulatory
fragment (URF) and the proximal promoter 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-specific
expression, periportal localization, perinatal activation and induction
by glucocorticoids, and cAMP in transgenic mice. Before birth, the transgene is silent but can be induced by cAMP and glucocorticoids, indicating that these compounds are responsible for the activation of
expression at birth. A 102-bp glucocorticoid response unit within the
URF, containing binding sites for HNF3, C/EBP, and the
glucocorticoid receptor, is the main determinant of the
hepatocyte-specific and hormone-controlled activity. Additional
sequences are required for a productive interaction between this
minimal response unit and the core CPS promoter. These results show
that the 469-bp 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.
Department of Anatomy and Embryology and the
§ Genetically Modified Mice Facility, Academic Medical
Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
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