Fragile X syndrome, the most common heritable form of mental retardation, is caused by silencing of the FMR1 (fragile X mental retardation-1 gene). The protein product of this gene, FMRP (fragile X mental retardation protein), is thought to be involved in the translational regulation of mRNAs important for learning and memory. In mammals, there are two homologues of FMRP, namely FXR1P (fragile X-related protein 1) and FXR2P. Disruption of Fxr2 in mice produces learning and memory deficits, and Fmr1 and Fxr2 double-knockout mice have exaggerated impairments in certain neurobehavioral phenotypes relative to the single gene knockouts. This has led to the suggestion that FMR1 and FXR2 functionally overlap and that increasing the expression of FXR2P may ameliorate the symptoms of an FMRP deficiency. Interestingly, the region upstream of the FXR2 translation start site acts as a bidirectional promoter in rodents, driving transcription of an alternative transcript encoding the ABP (androgen-binding protein) [aABP (alternative ABP promoter)]. To understand the regulation of the human FXR2 gene, we cloned the evolutionarily conserved region upstream of the FXR2 translation start site and showed that it also has bidirectional promoter activity in both neuronal and muscle cells as evidenced by luciferase reporter assay studies. Alignment of the human, mouse, rat, rabbit and dog promoters reveals several highly conserved transcription factor-binding sites. Gel electrophoretic mobility-shift assays, chromatin immunoprecipitation studies and co-transfection experiments with plasmids expressing these transcription factors or dominant-negative versions of these factors showed that NF-YA (nuclear transcription factor Yα), AP2 (activator protein 2), Nrf1 (nuclear respiratory factor/α-Pal) and Sp1 (specificity protein 1) all bind to the FXR2 promoter both in vitro and in vivo and positively regulate the FXR2 promoter.
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Research Article| November 14 2006
NF-Y, AP2, Nrf1 and Sp1 regulate the fragile X-related gene 2 (FXR2)
Karen Usdin 1
1Gene Structure and Disease Section, NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases), NIH (National Institutes of Health), Bethesda, MD 20892-0830, U.S.A.
1To whom correspondence should be addressed (email firstname.lastname@example.org).
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Lata Mahishi, Karen Usdin; NF-Y, AP2, Nrf1 and Sp1 regulate the fragile X-related gene 2 (FXR2). Biochem J 1 December 2006; 400 (2): 327–335. doi: https://doi.org/10.1042/BJ20060734
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