TY - JOUR
T1 - p53 Signaling Pathway Polymorphisms Associated With Emphysematous Changes in Patients With COPD
AU - Mizuno, Shiro
AU - Ishizaki, Takeshi
AU - Kadowaki, Maiko
AU - Akai, Masaya
AU - Shiozaki, Kohei
AU - Iguchi, Masaharu
AU - Oikawa, Taku
AU - Nakagawa, Ken
AU - Osanai, Kazuhiro
AU - Toga, Hirohisa
AU - Gomez-Arroyo, Jose
AU - Kraskauskas, Donatas
AU - Cool, Carlyne D.
AU - Bogaard, Herman J.
AU - Voelkel, Norbert F.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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.
AB - 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.
KW - cigarette smoke extract
KW - low attenuation area
KW - lung fibroblast
KW - mouse double minute 2 homolog
UR - http://www.scopus.com/inward/record.url?scp=85022101032&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.chest.2017.03.012
DO - https://doi.org/10.1016/j.chest.2017.03.012
M3 - Article
C2 - 28315337
SN - 0012-3692
VL - 152
SP - 58
EP - 69
JO - Chest
JF - Chest
IS - 1
ER -