p53 Signaling Pathway Polymorphisms Associated With Emphysematous Changes in Patients With COPD.
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.



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.



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.



Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan. Electronic address: shirotan@qf6.so-net.ne.jp.
Shiro
S
Mizuno
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Takeshi
T
Ishizaki
Department of Respiratory Medicine, University of Fukui, Fukui, Japan.
Maiko
M
Kadowaki
Department of Respiratory Medicine, Fukui Red Cross Hospital, Fukui, Japan.
Masaya
M
Akai
Department of Respiratory Medicine, Fukui Red Cross Hospital, Fukui, Japan.
Kohei
K
Shiozaki
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Masaharu
M
Iguchi
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Taku
T
Oikawa
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Ken
K
Nakagawa
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Kazuhiro
K
Osanai
Department of Respiratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
Hirohisa
H
Toga
Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA.
Jose
J
Gomez-Arroyo
Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA.
Donatas
D
Kraskauskas
Department of Pathology, University of Colorado Health Science Center, Lung Tissue Repository Consortium Repository, Aurora, CO.
Carlyne D
CD
Cool
VU University Medical Center, Amsterdam, The Netherlands.
Herman J
HJ
Bogaard
Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA.
Norbert F
NF
Voelkel
D000368:Aged; D004646:Emphysema / Q000235:genetics / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D012129:Respiratory Function Tests / Q000379:methods; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
cigarette smoke extract; low attenuation area; lung fibroblast; mouse double minute 2 homolog