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Environ Health Perspect; DOI:10.1289/ehp.1306911

Acrolein-Exposed Normal Human Lung Fibroblasts in Vitro: Cellular Senescence, Enhanced Telomere Erosion, and Degradation of Werner’s Syndrome Protein

Jun-Ho Jang,1,2 Shannon Bruse,2 Salam Huneidi,3 Ronald M. Schrader,1 Martha M. Monick,3 Yong Lin,2 A. Brent Carter,3 Aloysius J. Klingelhutz,4 and Toru Nyunoya1,2
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1Division of Pulmonary, Critical Care Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, New Mexico, USA; 2Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA; 3Division of Pulmonary, Critical Care, Occupational Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA; 4Department of Microbiology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA
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This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Jang JH, Bruse S, Huneidi S, Schrader RM, Monick MM, Lin Y, Carter AB, Klingelhutz AJ, Nyunoya T. Acrolein-Exposed Normal Human Lung Fibroblasts in Vitro: Cellular Senescence, Enhanced Telomere Erosion, and Degradation of Werner’s Syndrome Protein. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1306911.

Received: 8 April 2013
Accepted: 15 April 2014
Advance Publication: 18 April 2014

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Abstract

Background: Acrolein is a carcinogenic and ubiquitous environmental hazard to human health. Acrolein activates the DNA damage response and induces apoptosis. However, little is known about the effects of acrolein on cellular senescence.

Objectives: In this study, we investigated whether acrolein induces cellular senescence in cultured normal human lung fibroblasts (NHLF).

Methods: We cultured NHLF in the presence or absence of acrolein and determined the effects of acrolein on cell proliferative capacity, senescence-associated β-galactosidase activity, the known senescence-inducing pathways (e.g., p53-p21), and telomere length.

Results: We found that acrolein induced cellular senescence by increasing both p53 and p21. siRNA-mediated knockdown of p53 attenuated acrolein-induced cellular senescence. Acrolein decreased Werner’s syndrome protein (WRN protein), a member of the RecQ helicase family involved in DNA repair and telomere maintenance. Acrolein-induced downregulation of WRN protein was rescued by p53 knockdown or proteasome inhibition. Finally, we found that acrolein accelerates p53-mediated telomere shortening.

Conclusions: These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein downregulation.


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