An extra copy of <i>p53</i> suppresses development of spontaneous Kras-driven but not radiation-induced cancer.

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 <i>LA-1 Kras^G12D</i> mice with <i>wild-type p53</i> or an extra copy of <i>p53</i> (<i>super p53</i>) 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 <i>p53</i> suppressed both Kras-driven lung tumor and lymphoma development in the absence of radiation. However, an additional copy of <i>p53</i> did not affect lymphoma development following low- or high-LET radiation exposure and was unable to suppress radiation-induced expansion of thymocytes with mutated <i>Kras</i>. Moreover, radiation exposure increased lung tumor size in <i>super p53</i> but not <i>wild-type p53</i> mice. These results demonstrate that although <i>p53</i> suppresses the development of spontaneous tumors expressing Kras^G12D, in the context of exposure to ionizing radiation, an extra copy of <i>p53</i> does not protect against radiation-induced lymphoma and may promote Kras^G12D mutant lung cancer.