title: Pax-2 and N-myc regulate epithelial cell proliferation and apoptosis in a positive autocrine feedback loop.
abstract: Both paired homeo box-2 (Pax-2) and N-myc genes play pivotal roles in renal morphogenesis via their effects on cell proliferation and differentiation, but whether and how they interact have not been addressed. In the present study, we investigated such a potential interaction using embryonic renal cells in vitro. Mouse embryonic mesenchymal (MK4) cells stably transfected with Pax-2 cDNA in sense (+) or antisense (-) orientation were used for experiments. Pax-2 promoter activity was monitored by luciferase assay. Reactive oxygen species (ROS) generation, cell proliferation, and cell apoptosis were evaluated. We found that Pax-2 and N-myc gene expression were upregulated and downregulated in Pax-2 (+) and Pax-2 (-) stable transformants, respectively. ROS generation and apoptosis were significantly reduced both in Pax-2 (+) transformants compared with Pax-2 (-) transformants and in naïve MK4 cells cultured in either normal- (5 mM) or high-glucose (25 mM) medium. Transient transfection of N-myc cDNA into Pax-2 (-) stable transformants restored Pax-2 gene expression and prevented ROS generation induced by high glucose. Our data demonstrate that Pax-2 gene overexpression prevents hyperglycemia-induced apoptosis, and N-myc appears to provide a positive autocrine feedback on Pax-2 gene expression in embryonic mesenchymal cells.
authors.affiliation: University of Montréal, Centre hospitalier de l'Université de Montréal (CHUM)- Hôtel-Dieu, 3850 Saint Urbain Street, Montréal, Québec, H2W 1T7, Canada. shao.ling.zhang@umontreal.ca
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Stella
authors.initials: S
authors.lastname: Tran
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Eirini
authors.initials: E
authors.lastname: Nestoridi
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hébert
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D019898:Autocrine Communication / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000196:embryology; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D051762:PAX2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species