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Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation.

Authors
  • Xie, Maohua1
  • Park, Dongkyoo1
  • Sica, Gabriel L2
  • Deng, Xingming1
  • 1 Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
  • 2 Department of Pathology and Laboratory Medicine, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Type
Published Article
Journal
Carcinogenesis
Publisher
Oxford University Press
Publication Date
Nov 13, 2020
Volume
41
Issue
11
Pages
1565–1575
Identifiers
DOI: 10.1093/carcin/bgaa021
PMID: 32157295
Source
Medline
Language
English
License
Unknown

Abstract

Space radiation is characterized by high-linear energy transfer (LET) ionizing radiation. The relationships between the early biological effects of space radiation and the probability of cancer in humans are poorly understood. Bcl2 not only functions as a potent antiapoptotic molecule but also as an oncogenic protein that induces DNA replication stress. To test the role and mechanism of Bcl2 in high-LET space radiation-induced lung carcinogenesis, we created lung-targeting Bcl2 transgenic C57BL/6 mice using the CC10 promoter to drive Bcl2 expression selectively in lung tissues. Intriguingly, lung-targeting transgenic Bcl2 inhibits ribonucleotide reductase activity, reduces dNTP pool size and retards DNA replication fork progression in mouse bronchial epithelial cells. After exposure of mice to space radiation derived from 56iron, 28silicon or protons, the incidence of lung cancer was significantly higher in lung-targeting Bcl2 transgenic mice than in wild-type mice, indicating that Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation. The findings provide some evidence for the relative effectiveness of space radiation and Bcl-2 at inducing lung cancer in mice. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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