title: Lack of p53 Ser389 phosphorylation predisposes mice to develop 2-acetylaminofluorene-induced bladder tumors but not ionizing radiation-induced lymphomas.
abstract: Cellular activity of the tumor suppressor protein p53 is primarily regulated by posttranslational modifications. Phosphorylation of the COOH terminus, including Ser389, is thought to result in a conformational change of the p53 protein, enhancing DNA binding and transcriptional activity. In vitro studies presented here show that, in addition to UV radiation, Ser389 is phosphorylated upon exposure to 2-acetylaminofluorene (2-AAF). Both agents induce bulky DNA adducts repaired by nucleotide excision repair (NER). In contrast, ionizing radiation, known to induce DNA damage not repaired by NER, does not result in Ser389 phosphorylation. Previously, we have shown that p53.S389A mutant mice, lacking the Ser389 phosphorylation site, are sensitive to developing UV-induced skin tumors. Here, we show that p53.S389A mice are also prone to developing 2-AAF-induced urinary bladder tumors, whereas no increased tumor response was found upon ionizing irradiation. These results provide evidence for our hypothesis that phosphorylation of Ser389 is important for activation of p53 to exert its function as a tumor suppressor not exclusively upon the presence of UV-induced DNA damage, but also upon exposure to other bulky adduct-inducing agents. Analysis of 2-AAF- and UV-induced tumors from p53.S389A mice revealed the presence of additional p53 mutations, indicating that lack of Ser389 phosphorylation by itself is not sufficient to abrogate p53 function in tumor suppression. In addition, analyses of skin tumors of p53.S389A mice revealed an interesting hotspot mutation previously found exclusively in NER-deficient mice and patients.
authors.affiliation: National Institute of Public Health and the Environment, Laboratory of Toxicology, Pathology, and Genetics, Bilthoven, The Netherlands.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Hoogervorst
authors.forename: Wendy
authors.initials: W
authors.lastname: Bruins
authors.forename: Edwin
authors.initials: E
authors.lastname: Zwart
authors.forename: Conny Th M
authors.initials: CT
authors.lastname: van Oostrom
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: van den Aardweg
authors.forename: Rudolf B
authors.initials: RB
authors.lastname: Beems
authors.forename: Jolanda
authors.initials: J
authors.lastname: van den Berg
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Annemieke
authors.initials: A
authors.lastname: de Vries
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D005260:Female; D016158:Genes, p53 / Q000528:radiation effects; D008223:Lymphoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D012694:Serine; D015073:2-Acetylaminofluorene