A single regulatory module of the carbamoylphosphate synthetase I gene executes its hepatic program of expression
A single regulatory module of the carbamoylphosphate synthetase I gene executes its hepatic program of expression
复制标题
DOI：
10.1074/jbc.m007001200
复制
发表时间：
2000-12-22
影响因子：
4.8
通讯作者：
Lamers, WH
中科院分区：
文献类型：
--
作者：
Christoffels, VM;Habets, PEMH;Lamers, WH
一个469个碱基对（bp）的上游调控片段（URF）和近端启动子的氨甲酰磷酸合成酶I（CPS）基因进行了分析，其在空间，发育，并在体内的表达诱导的调节作用。URF对于转基因小鼠中肝细胞特异性表达、门静脉周围定位、围产期糖皮质激素和cAMP的激活和诱导是必需的和足够的。在出生前，转基因是沉默的，但可以被cAMP和糖皮质激素诱导，表明这些化合物是出生时激活表达的原因。URF内的102-bp糖皮质激素反应单位，含有HNF 3、C/EBP和糖皮质激素受体的结合位点，是肝细胞特异性和糖皮质激素控制活性的主要决定因素。需要额外的序列来实现该最小响应单元与核心CPS启动子之间的有效相互作用。这些结果表明，469 bp的URF，可能只有102 bp的糖皮质激素反应单位，作为一个监管模块的功能，因为它自主执行正确的空间，发育和激素程序的CPS在肝脏中的表达。
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.