Shiro Mizuno1, Takeshi Ishizaki2, Maiko Kadowaki3, Masaya Akai4, Kohei Shiozaki4, Masaharu Iguchi2, Taku Oikawa2, Ken Nakagawa2, Kazuhiro Osanai2, Hirohisa Toga2, Jose Gomez-Arroyo5, Donatas Kraskauskas5, Carlyne D Cool6, Herman J Bogaard7, Norbert F Voelkel5. 1. Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan. Electronic address: shirotan@qf6.so-net.ne.jp. 2. Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan. 3. Department of Respiratory Medicine, University of Fukui, Fukui, Japan. 4. Department of Respiratory Medicine, Fukui Red Cross Hospital, Fukui, Japan. 5. Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA. 6. Department of Pathology, University of Colorado Health Science Center, Lung Tissue Repository Consortium Repository, Aurora, CO. 7. VU University Medical Center, Amsterdam, The Netherlands.
Abstract
BACKGROUND: The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema. METHODS: This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured. RESULTS: The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE. CONCLUSIONS: Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.
BACKGROUND: The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema. METHODS: This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured. RESULTS: The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE. CONCLUSIONS: Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.
Authors: Li Zuo; Evan R Prather; Mykola Stetskiv; Davis E Garrison; James R Meade; Timotheus I Peace; Tingyang Zhou Journal: Int J Mol Sci Date: 2019-09-10 Impact factor: 5.923
Authors: Mikhlid H Almutairi; Bader O Almutairi; Turki M Alrubie; Sultan N Alharbi; Narasimha R Parine; Abdulwahed F Alrefaei; Ibrahim Aldeailej; Abdullah Alamri; Abdelhabib Semlali Journal: PLoS One Date: 2021-01-22 Impact factor: 3.240
Authors: J Ong; A Faiz; W Timens; M van den Berge; M M Terpstra; K Kok; A van den Berg; J Kluiver; C A Brandsma Journal: Sci Rep Date: 2019-12-03 Impact factor: 4.379