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Mol Carcinog. 2016 Sep;55(9):1387-96. doi: 10.1002/mc.22377. Epub 2015 Aug 27.

The Trp53 delta proline (Trp53ΔP) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
2
Department of Radiation Oncology, Department of Stem Cell Biology, Cleveland Clinic Main Campus, Cleveland, Ohio.
3
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
4
Department of Pathology, University of California San Francisco, San Francisco, California.
5
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
6
Department of Pathology and Laboratory Medicine, University of California Davis, Primate Drive, California.
7
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California.

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.

KEYWORDS:

Trp53; cancer radiation; genomic instability

PMID:
26310697
PMCID:
PMC4891300
DOI:
10.1002/mc.22377
[Indexed for MEDLINE]
Free PMC Article

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