LXR alpha functions as a cAMP-responsive transcriptional regulator of geneexpression

LXR alpha is a member of a nuclear receptor superfamily that regulates tran scription. LXR alpha forms a heterodimer with RXR alpha. another member of this family, to regulate the expression of cholesterol 7 alpha-hydroxylase by means of binding to the DR4-type cis-element. Here, we describe a functi on for LXR alpha as a cAMP-responsive regulator of renin and c-myc gene tra nscriptions by the interaction with a specific cis-acting DNA element, CNRE (an overlapping cAMP response element and a negative response element). Ou r previous studies showed that renin gene expression is regulated by cAMP, at least partly, through the CNRE sequence in its 5'-flanking region. This sequence is also found in c-myc and several other genes. Based on our cloni ng results using the yeast one-hybrid system, we discovered that the mouse homologue of human LXR alpha binds to the CNRE and demonstrated that it bin ds as a monomer. To define the function of LXR alpha on gene expression, we transfected the renin-producing renal As4.1 cells with LXR alpha expressio n plasmid. Overexpression of LXR alpha in As4.1 cells confers cAMP inducibi lity to reporter constructs containing the renin CNRE. After stable transfe ction of LXR alpha, As4.1 cells show a cAMP-inducible up-regulation of reni n mRNA expression. In parallel experiments, we demonstrated that LXR alpha can also bind to the homologous CNRE in the c-myc promoter. cAMP promotes t ranscription through c-myc/CNRE:LXR alpha interaction in LXR alpha transien tly transfected cells and increases c-myc mRNA expression in stably transfe cted cells. Identification of LXR alpha as a cAMP-responsive nuclear modula tor of renin and c-myc expression not only has cardiovascular significance but may have generalized implication in the regulation of gene transcriptio n.