Analysis of the cAMP response on liver‐specific gene expression in transgenic mice

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Abstract
Summary— Expression of many genes is modulated by intracellular variations of cyclic AMP (cAMP) levels in response to different signals from the environment. This regulation is mediated via a cAMP‐response element (CRE). This report addresses the role of cAMP in the physiological activation of a subset of liver‐specific genes which are perinatally activated. The tyrosine aminotransferase (TAT) gene and other genes such as phosphoenolpyruvate carboxyquinase (PEPCK) and glucose‐6‐phosphatase, involved in gluconeogenesis, belong to this category. CRE elements derived from the rat TAT −3.6 kb enhancer have been positioned in chimeric constructs, such that the activity of the reporter gene LacZ is dependent on cAMP. The tissue‐specificity of these constructs is guaranteed by the presence of the liver‐specific enhancers of the alpha fetoprotein gene. These constructs have been tested in cells and transgenic mice demonstrating cAMP regulation, liver‐specific expression and perinatal activation of the reporter gene. The CRE is recognized by a number of related proteins of which the cAMP‐response element‐binding factor (CREB) has been best studied. To assess the role of CREB in the in vivo transduction of cAMP signalling, mice deficient in CREB protein have been generated by homologous recombination in embryonic stem (ES) cells. Homozygous mutant mice, although recovering at a lower ratio than expected, do not display impairment of growth or development. The cAMP‐dependent LacZ transgenic mice in a CREB mutant genetic background also show perinatal activation of the reporter gene. Compensation with other members of the family of CRE‐binding proteins, such as cAMP‐response element modulator (CREM) or activating transcription factor‐1 (ATF‐1), may explain the lack of an obvious phenotype in CREB mutant mice.