FMR1 enhancer is regulated by cAMP through a cAMP-responsive element.
FMR1 (Fra X Mental Retardation 1), a gene of unknown function, is responsible for an important hereditary mental retardation, the fragile X syndrome. In this study, a 22-bp enhancer (methylation sensitive element, MSE) in the FMR1 promoter was defined by DNase I footprinting assay, and the binding of this element by nuclear factor was prevented by DNA CpG methylation. A cAMP-responsive element (CRE)-like sequence and a myc-binding sequence in MSE were identified. In the transfection assay, MSE demonstrated a strong, methylation-sensitive enhancer activity. MSE could be bound by recombinant CRE-binding protein (CREB), and its activity was stimulated by CREB in a co-transfection assay. In PC12 cells, forskolin elevated MSE activity several fold, and this induction was abolished in CRE mutants. The involvement of cAMP in the expression of FMR1 should be a clue to both the function of FMR1 and the pathogenesis of fragile X syndrome.
Hwu
W L
WL
Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, R.O.C.
Wang
T R
TR
Lee
Y M
YM
D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018983:DNA Footprinting; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics; D005786:Gene Expression Regulation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins; D012045:Regulatory Sequences, Nucleic Acid
D005576:Colforsin; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins