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An extra copy of p53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer
Everett J. Moding, … , Chang-Lung Lee, David G. Kirsch
Everett J. Moding, … , Chang-Lung Lee, David G. Kirsch
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e86698. https://doi.org/10.1172/jci.insight.86698.
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Research Article Oncology

An extra copy of p53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer

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Abstract

The tumor suppressor p53 blocks tumor progression in multiple tumor types. Radiation-induced cancer following exposure to radiation therapy or space travel may also be regulated by p53 because p53 has been proposed to respond to DNA damage to suppress tumorigenesis. Here, we investigate the role of p53 in lung carcinogenesis and lymphomagenesis in LA-1 KrasG12D mice with wild-type p53 or an extra copy of p53 (super p53) exposed to fractionated total body irradiation with low linear energy transfer (low-LET) X-rays or high-LET iron ions and compared tumor formation in these mice with unirradiated controls. We found that an additional copy of p53 suppressed both Kras-driven lung tumor and lymphoma development in the absence of radiation. However, an additional copy of p53 did not affect lymphoma development following low- or high-LET radiation exposure and was unable to suppress radiation-induced expansion of thymocytes with mutated Kras. Moreover, radiation exposure increased lung tumor size in super p53 but not wild-type p53 mice. These results demonstrate that although p53 suppresses the development of spontaneous tumors expressing KrasG12D, in the context of exposure to ionizing radiation, an extra copy of p53 does not protect against radiation-induced lymphoma and may promote KrasG12D mutant lung cancer.

Authors

Everett J. Moding, Hooney D. Min, Katherine D. Castle, Moiez Ali, Loretta Woodlief, Nerissa Williams, Yan Ma, Yongbaek Kim, Chang-Lung Lee, David G. Kirsch

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Figure 1

Exposure to fractionated X-ray radiation decreases survival of LA-1 mice.

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Exposure to fractionated X-ray radiation decreases survival of LA-1 mice...
(A) Relative p21 mRNA levels in the lungs of WT p53 and super p53 mice measured by qPCR 4 hours following exposure to no irradiation, 10 Gy X-rays, or 1 Gy 56Fe (n = 2). Data represent mean plus SEM. (B) Overall survival of WT p53 and super p53 mice following exposure to a single dose of 6 Gy X-rays. Overall survival of (C) LA-1; WT p53 and (D) LA-1; super p53 mice following exposure to no irradiation (No IR), 5 daily fractions of 1.2 Gy X-rays, or 5 daily fractions of 0.2 Gy 56Fe. *P < 0.05 by 2-way ANOVA followed by Bonferroni’s post-hoc test for A and Kaplan-Meyer analysis followed by log-rank test for B–D.

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