Cigarette smoke induces cellular senescence via Werner's syndrome protein down-regulation

Am J Respir Crit Care Med. 2009 Feb 15;179(4):279-87. doi: 10.1164/rccm.200802-320OC. Epub 2008 Nov 14.


Rationale: Werner's syndrome is a genetic disorder that causes premature aging due to loss-of-function mutations in a gene encoding a member of the RecQ helicase family. Both Werner's syndrome and cigarette smoking accelerate aging. No studies have examined the effect of cigarette smoke on Werner's syndrome protein.

Objectives: To investigate the role of Werner's syndrome protein in cigarette smoke-induced cellular senescence.

Methods: Cellular senescence and amounts of Werner's syndrome protein were measured in fibroblasts isolated from patients with emphysema and compared with age-matched nonsmokers. The in vitro effects of cigarette smoke on amounts of Werner's syndrome protein, function, and senescence were also evaluated in primary human lung fibroblasts and epithelial cells.

Measurements and main results: Cultured lung fibroblasts isolated from patients with emphysema exhibited a senescent phenotype accompanied by a decrease in Werner's syndrome protein. Cigarette smoke extract decreased Werner's syndrome protein in cultured fibroblasts and epithelial cells. Werner's syndrome protein-deficient fibroblasts were more susceptible to cigarette smoke-induced cellular senescence and cell migration impairment. In contrast, exogenous overexpression of Werner's syndrome protein attenuated the cigarette smoke effects.

Conclusions: Cigarette smoke induces cellular senescence and cell migration impairment via Werner's syndrome protein down-regulation. Rescue of Werner's syndrome protein down-regulation may represent a potential therapeutic target for smoking-related diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Culture Techniques
  • Cellular Senescence*
  • Down-Regulation
  • Exodeoxyribonucleases / metabolism*
  • Fibroblasts / metabolism*
  • Humans
  • Immunoblotting / methods
  • Lung / cytology
  • Lung / metabolism
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oxidative Stress
  • RecQ Helicases / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Tobacco Smoke Pollution*
  • Ubiquitin-Protein Ligases
  • Werner Syndrome / metabolism*
  • Werner Syndrome Helicase


  • Neoplasm Proteins
  • Nuclear Proteins
  • Tobacco Smoke Pollution
  • TOPORS protein, human
  • Ubiquitin-Protein Ligases
  • Exodeoxyribonucleases
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase