title: All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation.
abstract: All-trans retinoic acid (ATRA) is an active metabolite of Vitamin A, it shows protective effects on asthma, including maintains airway epithelial integrity, inhibits asthma effector cells differentiation, modulates immune response, et al. However, the promoting effect of ATRA on Th2 response has restricted the clinical application of ATRA in asthma treatment. ORMDL3 is a candidate gene of childhood onset asthma, and high-transcript of ORMDL3 is associated with the development of asthma. Here we show that ATRA increases ORMDL3 production in vitro via inducing PKA-dependent CREB phosphorylation which in turn binds to the CRE element in promoter region of ORMDL3 and initiates ORMDL3 transcription. This finding is in consistent with the previous reports that ATRA could regulate target genes without the presence of retinoic acid response element (RARE) in promoter region but through other signals such as PKA/CREB. Nevertheless, in the present study, the traditional signal pathway of ATRA, retinoic acid receptor (RAR) signal transduction pathway, indirectly modulated ORMDL3 expression. RAR-α agonist (Am-80) increased ORMDL3 production even though there was no RARE in ORMDL3 promoter, introns or 3'-downstream region. Besides, the signal of RAR might differ from that of ATRA since Am-80 failed to induce CREB activation. In conclusion, our data indicate that ATRA facilitates ORMDL3 production probable through PKA/CREB, and this may be a starting point for more detailed mechanism researches on ATRA and asthma.
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhuang
authors.forename: Bo-Xian
authors.initials: BX
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Feng
authors.forename: Liang-Hua
authors.initials: LH
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Jin
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Qiu
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Zhou
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D020413:3' Untranslated Regions; D001565:Benzoates; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D014212:Tretinoin; D017868:Cyclic AMP-Dependent Protein Kinases