| Project/Area Number |
12670337
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hygiene
|
|---|
| Research Institution | National Institute of Radiological Sciences |
|---|
Principal Investigator |
SHIMADA Yoshiya National Institute of Radiological Sciences, Low Dose Radiation Effect Project, Sub-Leader, 低線量プロジェクト, サブリーダー (10201550)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KAKINUMA Shizuko National Institute of Radiological Sciences, Low Dose Radiation Effect Project, Research Fellow, 低線量プロジェクト, リサーチフェロー
NISHIMURA Mayumi National Institute of Radiological Sciences, Low Dose Radiation Effect Project, Senior Researcher, 低線量プロジェクト, 主任研究員 (70218204)
|
|---|
| Project Period (FY) |
2000 – 2002
|
| Project Status |
Completed (Fiscal Year 2002)
|
| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
|
|---|
| Keywords | T-cell leukemia / LOH / Ikaros / mouse / radiation / ENU |
|---|
| Research Abstract |
To find the molecular pathways in radiation specific carcinogenesis, we determined the frequency and distribution of loss of heterozygosity (LOH), mutations of both Ikaros and K-ras genes, and methylation of p15 promoter of X-ray-induced thymic lymphomas (TL) of B6C3F1 mice and compared the results with those for spontaneous TL and N-ethylnitrosourea (ENU)-induced TL. We found a unique locus with frequent LOH in the centromeric region of chromosome 11 of X-ray-induced TL. This LOH has never been observed in either ENU-induced or spontaneous TLs, suggesting radiation-specific alteration. Linkage analysis revealed that the locus was genetically linked to Ikaros (Znflal), a master gene of lymphopoiesis. Ikaros was altered in 50% of TLs by a variety of mechanisms : (1) null expression (14%) ; (2) expression of dominant-negative isoforms(11%) ; (3) missense mutation in zinc-finger domain for DNA binding (22%) ; (4) lack of Ikaros isoform-1 due to an insertion of a dinucletotide. In contrast, only missense mutation was found in ENU-induced TL. Interestingly, Ikaros point mutation accompanied LOH in most of radiation-induced TL, losing expression of wild-type Ikaros protein, whereas small proportion of ENU-induced TL with Ikaros mutation lost expression of wild-type Ikaros. Next, methylation of p15 gene promoter was examined. While normal thymocytes did not show any methylation, the cells from TL showed distinct inter- and intra-tumor heterogeneity of methylation pattern. Methylation occurred more frequently in X-ray-induced TL than ENU-induced TL. There were several CpG sites where methylation was detected in only X-ray-induced TL, suggesting an existence of radiation-related CpG methylation. The frequency and spectrum of K-ras gene mutation, however, differed little between TLs. These results demonstrate that both Ikaros mutation with allelic loss of wild-type Ikaros and methylation of CpG of p15 gene promoter appear to be linked to radiation exposure.
|
