Academic Journal
Transcriptional regulation of the human FPR2/ALX gene : evidence of a heritable genetic variant that impairs promoter activity
| العنوان: | Transcriptional regulation of the human FPR2/ALX gene : evidence of a heritable genetic variant that impairs promoter activity |
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| المؤلفون: | F. Simiele, A. Recchiuti, D. Mattoscio, A. De Luca, E. Cianci, S. Franchi, V. Gatta, J. P. Werba, B. Favaloro, M. Romano, A. Parolari, M. Camera |
| المساهمون: | F. Simiele, A. Recchiuti, D. Mattoscio, A. De Luca, E. Cianci, S. Franchi, V. Gatta, A. Parolari, J.P. Werba, M. Camera, B. Favaloro, M. Romano |
| بيانات النشر: | Federation of American Societies for Experimental Biology |
| سنة النشر: | 2012 |
| المجموعة: | The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| مصطلحات موضوعية: | Inflammation, Lipoxin A 4 receptor, Methylation, Polymorphism, Sp1, Settore MED/23 - Chirurgia Cardiaca, Settore BIO/14 - Farmacologia |
| الوصف: | Lipoxin (LX) A(4), a main endogenous stop-signal of inflammation, activates the G-protein-coupled receptor FPR2/ALX, which triggers potent anti-inflammatory signaling in vivo. Thus, the regulation of FPR2/ALX expression may have pathophysiological and therapeutic relevance. Here, we mapped a nucleotide sequence with strong FPR2/ALX promoter activity. Chromatin immunoprecipitation revealed specificity protein 1 (Sp1) binding to the core promoter. Site-directed mutagenesis of the Sp1 cis-acting element and Sp1 overexpression established that this transcription factor is key for maximal promoter activity, which is instead suppressed by DNA methylation. LXA(4) enhanced FPR2/ALX promoter activity (+74%) and mRNA expression (+87.5%) in MDA-MB231 cells. A single nucleotide mutation (A/G) was detected in the core promoter of one subject with history of cardiovascular disease and of his two daughters. This mutation reduced by ∼35-90% the promoter activity in vitro. Moreover, neutrophils from individuals carrying the A/G variant displayed ∼10- and 3-fold reduction in FPR2/ALX mRNA and protein, respectively, compared with cells from their relatives or healthy volunteers expressing the wild-type allele. These results uncover FPR2/ALX transcriptional regulation and provide the first evidence of mutations that affect FPR2/ALX transcription, thus opening new opportunities for the understanding of the LXA(4)-FPR2/ALX axis in human disease -Simiele, F., Recchiuti, A., Mattoscio, D., De Luca, A., Cianci, E., Franchi, S., Gatta, V., Parolari, A., Werba, J. P., Camera, M., Favaloro, B., Romano, M. Transcriptional regulation of the human FPR2/ALX gene: Evidence of a heritable genetic variant that impairs promoter activity. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/22131270; info:eu-repo/semantics/altIdentifier/wos/WOS:000300949300034; volume:26; issue:3; firstpage:1323; lastpage:1333; journal:THE FASEB JOURNAL; http://hdl.handle.net/2434/170430; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84857752617 |
| DOI: | 10.1096/fj.11-198069 |
| الاتاحة: | http://hdl.handle.net/2434/170430 https://doi.org/10.1096/fj.11-198069 |
| رقم الانضمام: | edsbas.40EA51D6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1096/fj.11-198069 |
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