title: The Trp53 delta proline (Trp53ΔP) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development.
abstract: The tumor suppressor TP53 can initiate a plethora of anti-proliferative effects to maintain genomic integrity under conditions of genotoxic stress. The N-terminal proline-rich domain (PRD) of TP53 is important in the regulation of TP53 activity and stability. A common polymorphism at codon 72 in this region has been associated with altered cancer risk in humans. The Trp53ΔP mouse, which carries a germline homozygous deletion of a region of the PRD, does not develop spontaneous tumors in a mixed 129/Sv and C57BL/6 genetic background, but is highly susceptible to a broad range of tumor types following total body exposure to 4 Gy gamma (γ) radiation. This contrasts with the tumor spectrum in Trp53 null (-/-) mice, which mainly develop thymic lymphomas and osteosarcomas. Analysis of genomic instability in tissues and cells from Trp53ΔP mice demonstrated elevated basal levels of aneuploidy, but this is not sufficient to drive spontaneous tumorigenesis, which requires an additional DNA damage stimulus. Levels of genomic instability did not increase significantly in Trp53ΔP mice following irradiation exposure, suggesting that other radiation effects including tissue inflammation, altered metabolism or autophagy, may play an important role. The Trp53ΔP mouse is a novel model to dissect the mechanisms of tumor development induced by radiation exposure. © 2015 Wiley Periodicals, Inc.
authors: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors: Cassandra J
authors: CJ
authors: Adams
authors: Department of Radiation Oncology, Department of Stem Cell Biology, Cleveland Clinic Main Campus, Cleveland, Ohio.
authors: Jennifer S
authors: JS
authors: Yu
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors: Jian-Hua
authors: JH
authors: Mao
authors: Department of Pathology, University of California San Francisco, San Francisco, California.
authors: Kuang-Yu
authors: KY
authors: Jen
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors: Sylvain V
authors: SV
authors: Costes
authors: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors: Mark
authors: M
authors: Wade
authors: Department of Radiation Oncology, Department of Stem Cell Biology, Cleveland Clinic Main Campus, Cleveland, Ohio.
authors: Jocelyn
authors: J
authors: Shoemake
authors: Department of Pathology and Laboratory Medicine, University of California Davis, Primate Drive, California.
authors: Olulanu H
authors: OH
authors: Aina
authors: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors: Reyno
authors: R
authors: Del Rosario
authors: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors: Phuong Thuy
authors: PT
authors: Menchavez
authors: Department of Pathology and Laboratory Medicine, University of California Davis, Primate Drive, California.
authors: Robert D
authors: RD
authors: Cardiff
authors: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California.
authors: Geoffrey M
authors: GM
authors: Wahl
authors: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors: Allan
authors: A
authors: Balmain
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D063646:Carcinogenesis / Q000235:genetics*; D005260:Female; D005720:Gamma Rays; D042822:Genomic Instability; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D011123:Polyploidy; D011392:Proline / Q000737:chemistry / Q000235:genetics; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D011392:Proline
keywords: Trp53; cancer radiation; genomic instability