Abstract
Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211-phosphorylated PCNA. Cell extracts derived from arsenic-treated HeLa cells are defective in MMR, and unphosphorylated recombinant PCNA restores normal MMR activity to these extracts. These results suggest a model in which arsenic induces expression of EGFR, which in turn phosphorylates PCNA, and phosphorylated PCNA then inhibits MMR, leading to increased susceptibility to carcinogenesis. This study suggests a putative novel mechanism of action for arsenic and other non-genotoxic carcinogens.
Document Type
Article
Publication Date
6-5-2015
Digital Object Identifier (DOI)
https://doi.org/10.1074/jbc.M115.641399
Funding Information
This work was supported in part by grants from the National Cancer Institute (CA167181), National Institutes of Health, of the United States, the National Natural Science Foundation of China (31370766, 31461143005, and 30740420548), and Kentucky Lung Cancer Research program.
Janice Ortega was supported by a National Cancer Institute training grant (T32 CA165990).
Repository Citation
Tong, Dan; Ortega, Janice; Kim, Christine; Huang, Jian; Gu, Liya; and Li, Guo-Min, "Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation" (2015). Toxicology and Cancer Biology Faculty Publications. 52.
https://uknowledge.uky.edu/toxicology_facpub/52
Notes/Citation Information
Published in The Journal of Biological Chemistry, v. 290, no. 23, p. 14536-14541.
This research was originally published in The Journal of Biological Chemistry. Dan Tong, Janice Ortega, Christine Kim, Jian Huang, Liya Gu, and Guo-Min Li. Title. The Journal of Biological Chemistry. 2015; 290:14536-14541. © the American Society for Biochemistry and Molecular Biology.
The copyright holder has granted the permission for posting the article here.