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ABSTRACT The p53 tumor suppressor protein inhibits proliferation by inducing either cell cycle arrest or apoptosis in response to cellular stresses. Mouse embryo fibroblasts (MEFs) provide a
primary cell model system in which to examine both functions of p53. MEFs treated with gamma-rays undergo p53-dependent G1 arrest, while oncogene-expressing MEFs treated with a variety of
DNA-damaging agents undergo p53-dependent apoptosis. Although the p53-dependent G1 arrest checkpoint response to gamma-rays in MEFs has been well characterized, the response to other
DNA-damaging agents has not. Here, we examine the effects of commonly utilized chemotherapeutics, including doxorubicin, etoposide, and cisplatin, on cell cycle arrest in MEFs, and we define
the p53 dependence of these effects. In addition, we examine the response of MEFs to ultraviolet light (UVC), as a representative agent acting by inducing pyrimidine dimers. Although p53 is
clearly activated by all the agents examined, as measured by p21 induction, there are surprising differences in the activities of these agents. For example, doxorubicin but not cisplatin
can effectively induce a p53-dependent G1 arrest. UVC, in contrast, induces a p53-independent G1 arrest response. Thus, the exact response of cells to DNA damage depends on the specific
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ACKNOWLEDGEMENTS We thank J Sage, J Brugarolas, E Flores, A Giaccia, M Brown, G Chu, G Wahl, S Lowe, K Cimprich, S Artandi, R Ihrie, and T Johnson for critical reading of the manuscript.
This work has been supported by the American Cancer Society, the Bunting Institute at Radcliffe College, Merck, and the Damon Runyon Cancer Research Foundation to LDA and by the Dutch Cancer
Society to ADV. This work has been supported by the HHMI and NCI funding to TJ. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Radiation Oncology and Department of Genetics,
Stanford University School of Medicine, Stanford, 94305-5152, CA, USA Laura D Attardi * Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health, Bilthoven, 3720
BA, The Netherlands Annemieke de Vries * Department of Biology, MIT, Cambridge, 02139, MA, USA Tyler Jacks * Howard Hughes Medical Institute, MIT, Cambridge, 02139, MA, USA Tyler Jacks
Authors * Laura D Attardi View author publications You can also search for this author inPubMed Google Scholar * Annemieke de Vries View author publications You can also search for this
author inPubMed Google Scholar * Tyler Jacks View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Laura D Attardi.
RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Attardi, L., de Vries, A. & Jacks, T. Activation of the p53-dependent G1 checkpoint response in mouse
embryo fibroblasts depends on the specific DNA damage inducer. _Oncogene_ 23, 973–980 (2004). https://doi.org/10.1038/sj.onc.1207026 Download citation * Received: 12 May 2003 * Revised: 18
July 2003 * Accepted: 21 July 2003 * Published: 29 January 2004 * Issue Date: 29 January 2004 * DOI: https://doi.org/10.1038/sj.onc.1207026 SHARE THIS ARTICLE Anyone you share the following
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SharedIt content-sharing initiative KEYWORDS * p53 * cell cycle arrest * apoptosis * chemotherapeutics * DNA damage