title: ATF3 represses PPARγ expression and inhibits adipocyte differentiation.
abstract: Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of -2.6Kb promoter of mouse PPARγ2. Overexpression of PPARγ significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5' deleted-reporters showed that ATF3 repressed the activity of -2037bp promoter, whereas it did not affect the activity of -1458bp promoter, suggesting that ATF3 responsive element is located between the -2037 and -1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5'-TGACGTTT-3') between -1537 and -1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARγ2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARγ expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARγ expression. Furthermore, overexpression of PPARγ prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated inhibition of PPARγ expression may contribute to inhibition of adipocyte differentiation during cellular stress including ER stress.
authors.affiliation: School of Korean Medicine, Pusan National University, #49 Busandae hak-ro, Mulguem-eup, Yangsan-si, Gyeongnam 609-735, South Korea.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Jang
authors.affiliation: School of Korean Medicine, Pusan National University, #49 Busandae hak-ro, Mulguem-eup, Yangsan-si, Gyeongnam 609-735, South Korea. Electronic address: jung0603@pusan.ac.kr.
authors.forename: Myeong Ho
authors.initials: MH
authors.lastname: Jung
mesh_terms: D041721:3T3-L1 Cells; D051700:Activating Transcription Factor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D047495:PPAR gamma; D019284:Thapsigargin
keywords: ATF/CREB responsive element (ATF/CRE); Activating transcription factor 3 (ATF3); Adipocyte differentiation; Peroxisome proliferator activated receptor γ (PPARγ); Promoter activity