| Project/Area Number |
08680915
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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 |
Laboratory animal science
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
KOBAYASHI Toshiyuki Cancer Institute, Dept.of Experimental Pathology, Associate, 癌研究所・実験病理部, 研究員 (40260070)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1996: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Eker rat / Hereditary tumoar / Renal cancer / Embryonic lethality / Tsc2 gene / Transgenic rat |
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| Research Abstract |
We have identified a predisposing germline mutation for the Eker rat hereditary renal carcinoma in the rat homelog of human tuberous sclerosis 2 gene (TSC2). Also we have indentified somatic mutations and deletions on the wild-type Tsc2 allel (second hits) in renal carcinomas and even in preneoplastic lesions fom the Eker rat, indicating that the Tsc2 gene functions as a tumor suppressor. In tahis study, an attempt to suppress phenotypes of the Eker rat, the renal carcinogenesis in heterozygotes for Tsc2mutataion and the embryonic lethality in homozygous Tsc2 mutants, was carried out by introduction of a wild-type Tsc2 transgere. The transgene used here consisted of a wild-type rat Tsc2 cDNA (lacking exons 25 and 31 by alternative splicing events) and genomic DNA,and was driven by Tsc2 promoter. By idntroduction of this transgene, both of renalcarcinogenesis and embryonic lethality were successfully suppressed in the Eker rat. These results are final evidence to define the germline mutataion of Tsc2 gene as the cause of Eker rat phenotypes. Interesltingly, rescued homozygous Tsc2 mdutants developed renal tumors as well as pituitary tumors, which often developed in the Eker draats. In these tumors, the wild-type Tsc2 transgene was somatically deleted, indicating that the initiation of these tumors was caused by loss of Tsc2 function. the transgenic rescue for the Eker rat phenotype established in this study will be a usefull in vivo experimental system to analyze the function of Tsc2 gene and its product, and to elucidate molecular mechanism of tumorigenesis caused gy Tsc2 mdutations.
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