Ikaros is a critical target during simultaneous exposure to X-rays and N-ethyl-N-nitrosourea in mouse T-cell lymphomagenesis.
Cancer risk associated with radiation exposure is considered the result of concurrent exposure to other natural and manmade carcinogens. Available data on the molecular characteristics of cancer after simultaneous exposure to radiation and chemicals are insufficient. In our study, we used a mouse thymic lymphoma (TL) model that was synergistically induced by simultaneous exposure to X-rays and N-ethyl-N-nitrosourea (ENU) at subcarcinogenic doses and analyzed the mutation frequency and spectrum of the TL-associated genes Ikaros, Notch1, p53 and Kras. We found that the point mutation frequency in Ikaros was significantly increased to 47% for simultaneous exposure compared to 13 and 0% for X-ray and ENU exposure alone, respectively. These mutations were mostly G:C > A:T at non-CpG sites and T:A > C:G, both of which are characteristic of ENU mutagenesis. About half of the point mutations were accompanied by loss of heterozygosity (LOH), typical of X-irradiation. The remaining half did not include LOH, which suggests that they were dominant-negative mutations. In Notch1, the frequency of abnormalities was high (>58%) regardless of the treatment, suggesting that Notch1 aberration may be important for T-cell lymphomagenesis. The p53 and Kras mutation frequencies were low for all treatments (<23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both Ikaros and Notch1, increased after simultaneous exposure. Thus, after simultaneous exposure, Ikaros is a critical target and is inactivated by ENU-induced point mutations and/or X-ray-induced LOH in T-cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor-associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.
Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Inage-Ku, Chiba, Japan.
Shinobu
S
Hirano
Shizuko
S
Kakinuma
Yoshiko
Y
Amasaki
Mayumi
M
Nishimura
Tatsuhiko
T
Imaoka
Shinji
S
Fujimoto
Okio
O
Hino
Yoshiya
Y
Shimada
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000528:radiation effects; D004252:DNA Mutational Analysis; D005038:Ethylnitrosourea; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000235:genetics*; D019656:Loss of Heterozygosity; D016399:Lymphoma, T-Cell / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017354:Point Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014965:X-Rays
D051792:Basic Helix-Loop-Helix Proteins; D005038:Ethylnitrosourea; D018398:Homeodomain Proteins; D051740:Ikaros Transcription Factor; D016283:Proto-Oncogene Proteins p21(ras); D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D016159:Tumor Suppressor Protein p53; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C497238:Zfpn1a1 protein, mouse; C495971:Hras protein, mouse