title: The specificity protein factor Sp1 mediates transcriptional regulation of P2X7 receptors in the nervous system.
abstract: P2X7 receptors are involved not only in physiological functions but also in pathological brain processes. Although an increasing number of findings indicate that altered receptor expression has a causative role in neurodegenerative diseases and cancer, little is known about how expression of P2rx7 gene is controlled. Here we reported the first molecular and functional evidence that Specificity protein 1 (Sp1) transcription factor plays a pivotal role in the transcriptional regulation of P2X7 receptor. We delimited a minimal region in the murine P2rx7 promoter containing four SP1 sites, two of them being highly conserved in mammals. The functionality of these SP1 sites was confirmed by site-directed mutagenesis and Sp1 overexpression/down-regulation in neuroblastoma cells. Inhibition of Sp1-mediated transcriptional activation by mithramycin A reduced endogenous P2X7 receptor levels in primary cultures of cortical neurons and astrocytes. Using P2rx7-EGFP transgenic mice that express enhanced green fluorescent protein under the control of P2rx7 promoter, we found a high correlation between reporter expression and Sp1 levels in the brain, demonstrating that Sp1 is a key element in the transcriptional regulation of P2X7 receptor in the nervous system. Finally, we found that Sp1 mediates P2X7 receptor up-regulation in neuroblastoma cells cultured in the absence of serum, a condition that enhances chromatin accessibility and facilitates the exposure of SP1 binding sites.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: García-Huerta
authors.forename: Miguel
authors.initials: M
authors.lastname: Díaz-Hernandez
authors.forename: Esmerilda G
authors.initials: EG
authors.lastname: Delicado
authors.forename: María
authors.initials: M
authors.lastname: Pimentel-Santillana
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.forename: Rosa
authors.initials: R
authors.lastname: Gómez-Villafuertes
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009420:Nervous System / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011401:Promoter Regions, Genetic; D058486:Receptors, Purinergic P2X7 / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D058486:Receptors, Purinergic P2X7; D016329:Sp1 Transcription Factor