2000 Fiscal Year Final Research Report Summary
Genetic analyses for apoptosis susceptibility and identification of genes involved
| Project/Area Number |
10680521
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
環境影響評価(含放射線生物学)
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| Research Institution | Osaka Prefecture University |
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Principal Investigator |
MORI Nobuko Osaka Prefecture University, Research Institute for Advanced Science & Technology, Research Associate, 先端科学研究所, 助手 (90100221)
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| Co-Investigator(Kenkyū-buntansha) |
OKUMOTO Masaaki Osaka Prefecture University, Research Institute for Advanced Science & Technology, Professor, 先端科学研究所, 教授 (50100186)
YAMATE Joji Osaka Prefecture University, College of Agriculture, Associate Professor, 農学部, 助教授 (50150115)
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| Project Period (FY) |
1998 – 2000
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| Keywords | apoptosis / apoptosis susceptibility / genetic analysis / mouse / thymus / radiation / radiation lymphomagenesis |
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| Research Abstract |
This study was aimed at fine mapping and identification of apoptosis susceptibility genes Rapop1, Rapop2 and Rapop3, which had been mapped on mouse chromosomes 16.9 and 3 respectively as well as at analyses of apoptosis susceptibility. The STS allele at any of these loci decreases radiation-induced apoptosis of thymocytes in the BALB/c background. Both Rapop1 and Rapop2 have been suggested to be also involved in radiation-induced apoptosis in colon, but in a different way from that in the thymus. In addition, Rapop1 has been shown to affect steroid- as well as radiation-induced apoptosis in the thymus. p53 deficiency has been shown to enhance steroid-induced apoptosis. Analysis of several mice with recombination in the STS-derived segment of chromosome 16 in the BALB/c background showed that the critical region for Rapop1 was 0.45 cM near D16Mit34. Since DNA-PKcs, the catalytic subunit of DNA-dependent protein kinase (DNA-PK) critical for DNA double-strand break (dsb) repair, has been centered in this region, we tested DNA-PKcs as a potential candidate for Rapop1. On sequencing cDNAs for DNA-PKcs, two different variations producing amino acid substitutions between BALB/c and STS have been identified. Haplotype analysis for DNA-PKcs in number of inbred strains showed that the majority carried the STS allele, indicating that the STS allele was wild type. DNA-PK activity was pronouncedly diminished in the mice with the BALB/c allele at DNA-PKcs, concomitant with decreased DNA-PKcs expression at the similar levels of mRNA.Rapop1 congenic mice that carried the STS allele at DNA-PKcs in the BALB/c background were less sensitive to both radiation-induced apoptosis and lymphomas as compared with BALB/c. This might be explained by different capability in dsb repair between DNA-PKcs haplotypes. The results strongly implicated DNA-PKcs as a candidate for Rapop1.
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