title: Activation of the p53-dependent G1 checkpoint response in mouse embryo fibroblasts depends on the specific DNA damage inducer.
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 agent used.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305-5152, USA. attardi@stanford.edu
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
authors.forename: Annemieke
authors.initials: A
authors.lastname: de Vries
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology* / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D016193:G1 Phase; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D017500:Adenovirus E1A Proteins; D016159:Tumor Suppressor Protein p53