title: Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation.
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.
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, China 430072, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and Tsinghua University School of Medicine, Beijing, China 100084.
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and.
authors.forename: Janice
authors.initials: J
authors.lastname: Ortega
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and.
authors.forename: Christine
authors.initials: C
authors.lastname: Kim
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, China 430072.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and.
authors.forename: Liya
authors.initials: L
authors.lastname: Gu
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, China 430072, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and Tsinghua University School of Medicine, Beijing, China 100084 gmli@uky.edu.
authors.forename: Guo-Min
authors.identifier: http://orcid.org/0000-0001-7953-0220
authors.initials: GM
authors.lastname: Li
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D063646:Carcinogenesis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D053843:DNA Mismatch Repair / Q000187:drug effects*; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; C512478:EGFR protein, human; D066246:ErbB Receptors; D001151:Arsenic
keywords: DNA mismatch repair; DNA repair; epidermal growth factor receptor (EGFR); nucleic acid; proliferating cell nuclear antigen (PCNA)