WEKO3
アイテム
Role of Exposure Sequence in the Combined Effect of Ionizing Radiation and N-ethyl-N-nitrosourea in Murine T-cell Lymhomagenesis
https://repo.qst.go.jp/records/62253
https://repo.qst.go.jp/records/622533ae0e875-fa2e-4ba7-b7a9-ddf3f6b6f85a
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2007-10-09 | |||||
| タイトル | ||||||
| タイトル | Role of Exposure Sequence in the Combined Effect of Ionizing Radiation and N-ethyl-N-nitrosourea in Murine T-cell Lymhomagenesis | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Kakinuma, Shizuko
× Kakinuma, Shizuko× Amasaki, Yoshiko× Yamauchi, Kazumi× Nishimura, Mayumi× Imaoka, Tatsuhiko× Shimada, Yoshiya× 柿沼 志津子× 甘崎 佳子× 山内 一己× 西村 まゆみ× 今岡 達彦× 島田 義也 |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Murine T-cell lymphomas (TL) can be reproducibly induced by ionizing radiation or chemical carcinogens. This animal model is considered useful in the search for characterization of genes involved in the development of human acute lymphoblastic leukemia. We have been studying this lymphoma model, which is induced by X-rays, carbon-ions or alkylating agents such as N-ethyl-N-nitrosourea (ENU). In the study of X-ray induced thymic lymphomas in B6C3F1 mice, we found a unique locus with a high frequency of loss of heterozygosity (LOH) (50%) in the centromeric region of chromosome 11 [1]. LOH at this locus was very rarely observed in ENU-induced or spontaneously developing T-cell lymphomas, suggesting that it was a radiation-associated molecular change. We also showed that Ikaros was mapped in this frequent LOH locus, suggesting Ikaros as a tumor suppressor gene. Ikaros is a transcription factor that plays a critical role in both lineage commitment and differentiation of lymphocytes. The mutation analysis of Ikaros in the X-ray- or ENU-induced lymphomas revealed that Ikaros mutation frequency and spectrum is carcinogen dependent. Mutation frequency in X-ray-induced TL was around 50%, while that in ENU-induced TL was 20%. Inactivation of Ikaros in X-ray-induced TL was caused by transcriptional silencing, unusual splicing, point mutation and small insertion, most of which were associated with LOH [2]. LOH at Ikaros locus was generated by intra-chromosomal deletion [3]. On the other hand, Ikaros inactivation in ENU-induced TLs was caused by only point mutations not accompanied with LOH [4]. Thus, the mutation of Ikaros was distinguished between X-rays-induced TL and ENU-induced one. Recently, we showed that TL induced in mismatch repair gene Mlh1-deficient mice harbored frequent frameshift mutations in mononucleotide sequence in Ikaros, suggesting Ikaros is also a mutational target in Mlh1-dificient mice [5]. Taken together, Ikaros could be inactivated by several mechanisms. Recently our interest is focused on the effect of combined exposure of radiation and chemical carcinogens. Since we are living in the environment with numerous natural and man-made radiation and chemicals, cancer development in human is considered as a result of interaction with these factors. But, the quantitative assessment and mechanistic understanding of combined effects of radiation and chemical carcinogens are still insufficient. The aim of this study is to elucidate the mode and mechanism of the combined effect of X-rays with ENU on mouse T-cell leukemogenesis. Beginning at 4- or 8-weeks of age, female B6C3F1 mice were exposed weekly to whole body X-irradiation (0.2 ? 2.0 Gy) for consecutive 4 weeks or were given ENU (50 ? 400 ppm) in drinking water for consecutive 4 weeks. The dose-response curve for X-ray- or ENU?induced lymphoma had threshold dose. Combined exposure was carried out by X-irradiation followed by ENU or by reverse sequence ENU followed by X-irradiation. The exposure of high dose X-rays followed by ENU resulted in a synergistic effect, while the effect was antagonistic at low or threshold dose of carcinogens. Thus, combined effect is dose dependent. When the order of exposure was reversed, i.e., ENU followed by X-rays, the mode of combined exposure was additive at any doses. Molecular changes such as LOH and Ikaros mutations in TL after X-irradiation followed by ENU were similar to those in ENU-induced TL. In contrast, TL induced by reverse treatment exhibited mutations, which were similar to those found in X-ray-induced TL. It is concluded that the mode of combined effect is dependent upon the dose and the treatment order of carcinogens. \n1. Shimada Y., M. Nishimura, S. Kakinuma, M. Okumoto, T. Shiroishi, K. H. Clifton, S. Wakana: Radiation-associated loss of heterozygosity at the Znfn1a1 (Ikaros) locus on chromosome 11 in murine thymic lymphomas. Radiat Res 2000;154:293-300.? 2. Kakinuma S., M. Nishimura, S. Sasanuma, K. Mita, G. Suzuki, Y. Katsura, T. Sado, Y. Shimada: Spectrum of Znfn1a1 (Ikaros) inactivation and its association with loss of heterozygosity in radiogenic T-cell lymphomas in susceptible B6C3F1 mice. Radiat Res 2002;157:331-340.? 3. Yoshida M. A., A. Nakata, M. Akiyama, S. Kakinuma, T. Sado, M. Nishimura, Y. Shimada: Distinct structural abnormalities of chromosomes 11 and 12 associated with loss of heterozygosity in X-ray-induced mouse thymic lymphomas. Cancer Genet Cytogenet 2007: in press.? 4. Kakinuma S., M. Nishimura, A. Kubo, J. Y. Nagai, Y. Amasaki, H. J. Majima, T. Sado, Y. Shimada: Frequent retention of heterozygosity for point mutations in p53 and Ikaros in N-ethyl-N-nitrosourea-induced mouse thymic lymphomas. Mutat Res 2005;572:132-141.? 5. Kakinuma S., Y. Kodama, Y. Amasaki, S. Yi, Y. Tokairin, M. Arai, M. Nishimura, M. Monobe, S. Kojima, Y. Shimada: Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice. Oncogene 2007;26:2945-2949. |
|||||
| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | NIRS-Bfs Internatinal Workshop on Research Applications of the Radiationbiology Archives | |||||
| 発表年月日 | ||||||
| 日付 | 2007-07-24 | |||||
| 日付タイプ | Issued | |||||
