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Title: p53-dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts

Abstract

This study focused on the activation of cell cycle checkpoint responses in diploid human fibroblasts that were treated with cadmium chloride and the potential roles of ATM and p53 signaling pathways in cadmium-induced responses. The alkaline comet assay indicated that cadmium caused a dose-dependent increase in DNA damage. Cells that were rendered p53-defective by expression of a dominant-negative p53 allele or knockdown of p53 mRNA were more resistant to cadmium-induced inactivation of colony formation than normal and ataxia telangiectasia (AT) cells. Synchronized fibroblasts in S were more sensitive to cadmium toxicity than cells in G1, suggesting that cadmium may target some element of DNA replication. Cadmium produced a dose- and time-dependent inhibition of DNA synthesis. An immediate inhibition was associated with severe delay in progression through S phase and a delayed inhibition seen 24 h after treatment was associated with accumulation of cells in G2. AT and normal cells displayed similar patterns of inhibition of DNA synthesis and G2 delay after treatment with cadmium, while p53-defective cells displayed significantly less of the delayed inhibition of DNA synthesis and accumulation in G2 post-treatment. Total p53 protein and ser15-phosphorylated p53 were induced by cadmium in normal and AT cells. The p53 transactivationmore » target Gadd45{alpha} was induced in both p53-effective and p53-defective cells after 4 h cadmium treatment, and this was associated with an acute inhibition of mitosis. Cadmium produced a very unusual pattern of toxicity in human fibroblasts, inhibiting DNA replication and inducing p53-dependent growth arrest but without induction of p21{sup Cip1/Waf1} or activation of Chk1.« less

Authors:
 [1];  [2]; ;  [3];  [3];  [4];  [1];  [2];  [2]
  1. Dept. of Toxicology, School of Public Health, Medical Center of Fudan Univ., Shanghai (China)
  2. Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599 (United States)
  3. Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, North Carolina 27599 (United States)
  4. Department of Toxicology, School of Public Health, Medical Center of Fudan University, Shanghai (China)
Publication Date:
OSTI Identifier:
20976851
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 218; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2006.10.031; PII: S0041-008X(06)00411-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CADMIUM; CADMIUM CHLORIDES; CARBOXYLIC ACIDS; CELL CYCLE; CHLORINATED ALIPHATIC HYDROCARBONS; COLONY FORMATION; DEOXYURIDINE; DNA; DNA REPLICATION; FIBROBLASTS; INHIBITION; MITOSIS; PROTEINS; SODIUM; STRAND BREAKS; SULFATES; SYNTHESIS; TIME DEPENDENCE; TOXICITY

Citation Formats

Feng, Cao, Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599, Tong, Zhou, Simpson, Dennis, Yingchun, Zhou, Boyer, Jayne, Bo, Chen, Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599, Taiyi, Jin, Cordeiro-Stone, Marila, and Kaufmann, William. p53-dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts. United States: N. p., 2007. Web.
Feng, Cao, Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599, Tong, Zhou, Simpson, Dennis, Yingchun, Zhou, Boyer, Jayne, Bo, Chen, Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599, Taiyi, Jin, Cordeiro-Stone, Marila, & Kaufmann, William. p53-dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts. United States.
Feng, Cao, Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599, Tong, Zhou, Simpson, Dennis, Yingchun, Zhou, Boyer, Jayne, Bo, Chen, Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599, Taiyi, Jin, Cordeiro-Stone, Marila, and Kaufmann, William. 2007. "p53-dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts". United States.
@article{osti_20976851,
title = {p53-dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts},
author = {Feng, Cao and Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599 and Tong, Zhou and Simpson, Dennis and Yingchun, Zhou and Boyer, Jayne and Bo, Chen and Dept. of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, Univ. of North Carolina, Chapel Hill, North Carolina 27599 and Taiyi, Jin and Cordeiro-Stone, Marila and Kaufmann, William},
abstractNote = {This study focused on the activation of cell cycle checkpoint responses in diploid human fibroblasts that were treated with cadmium chloride and the potential roles of ATM and p53 signaling pathways in cadmium-induced responses. The alkaline comet assay indicated that cadmium caused a dose-dependent increase in DNA damage. Cells that were rendered p53-defective by expression of a dominant-negative p53 allele or knockdown of p53 mRNA were more resistant to cadmium-induced inactivation of colony formation than normal and ataxia telangiectasia (AT) cells. Synchronized fibroblasts in S were more sensitive to cadmium toxicity than cells in G1, suggesting that cadmium may target some element of DNA replication. Cadmium produced a dose- and time-dependent inhibition of DNA synthesis. An immediate inhibition was associated with severe delay in progression through S phase and a delayed inhibition seen 24 h after treatment was associated with accumulation of cells in G2. AT and normal cells displayed similar patterns of inhibition of DNA synthesis and G2 delay after treatment with cadmium, while p53-defective cells displayed significantly less of the delayed inhibition of DNA synthesis and accumulation in G2 post-treatment. Total p53 protein and ser15-phosphorylated p53 were induced by cadmium in normal and AT cells. The p53 transactivation target Gadd45{alpha} was induced in both p53-effective and p53-defective cells after 4 h cadmium treatment, and this was associated with an acute inhibition of mitosis. Cadmium produced a very unusual pattern of toxicity in human fibroblasts, inhibiting DNA replication and inducing p53-dependent growth arrest but without induction of p21{sup Cip1/Waf1} or activation of Chk1.},
doi = {},
url = {https://www.osti.gov/biblio/20976851}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 218,
place = {United States},
year = {Mon Jan 15 00:00:00 EST 2007},
month = {Mon Jan 15 00:00:00 EST 2007}
}