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Contribution of ATM and ATR kinase pathways to p53-mediated response in etoposide and methyl methanesulfonate induced DNA damage.
- Source :
-
Environmental and molecular mutagenesis [Environ Mol Mutagen] 2017 Mar; Vol. 58 (2), pp. 72-83. Date of Electronic Publication: 2017 Feb 14. - Publication Year :
- 2017
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Abstract
- p53 is a key integrator of cellular response to DNA damage, supporting post-translational repair and driving transcription-mediated responses including cell cycle arrest, apoptosis, and repair. DNA damage sensing kinases recognize different types of DNA damage and initiate specific responses through various post-translational modifications of p53. This study evaluated chemical specificity of the p53 pathway response by manipulating p53 or its upstream kinases and assessing the effect on DNA damage and cellular responses to prototype chemicals: etoposide (ETP, topoisomerase II inhibitor) and methyl methane sulfonate (MMS, alkylating agent). p53-deficient cells demonstrated reduced accumulation of the p53 target proteins MDM2, p21, and Wip1; reduced apoptotic response; and increased DNA damage (p-H2AX and micronuclei) with both chemicals. However, p53 was not essential for cell cycle arrest in HT1080 or HCT116 cells. The two chemicals induced different patterns of kinase activation, particularly in terms of Chk 1, Chk 2, p38, and ERK 1/2. However, inhibition of the ATM pathway showed a greater effect on p53 activtation, apoptosis, and accumulation of DNA damage than ATR-Chk 1 or the MAP kinases regardless of the chemical used. These results indicate that ATM is the predominant upstream kinase responsible for activation of the p53-mediated DNA damage response for both MMS and ETP, though the downstream kinase response is markedly different. Environ. Mol. Mutagen. 58:72-83, 2017. © 2017 Wiley Periodicals, Inc.<br /> (© 2017 Wiley Periodicals, Inc.)
- Subjects :
- Cell Cycle drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Flow Cytometry
Gene Knockdown Techniques
HCT116 Cells
Humans
Micronucleus Tests
Signal Transduction
Tumor Suppressor Protein p53 genetics
Apoptosis drug effects
Ataxia Telangiectasia Mutated Proteins metabolism
DNA Damage
Etoposide toxicity
Mesylates toxicity
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-2280
- Volume :
- 58
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Environmental and molecular mutagenesis
- Publication Type :
- Academic Journal
- Accession number :
- 28195382
- Full Text :
- https://doi.org/10.1002/em.22070