| Project/Area Number |
10671665
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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 |
Pediatric surgery
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| Research Institution | University of Tsukuba |
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Principal Investigator |
MICHIO Kaneko University of Tsukuba, Pediatric Surgery, Professor, 臨床医学系・小児外科, 教授 (60152807)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIO Watanabe Nagoya University, Pediatric Surgery, Associated Professor, 医学部・小児外科, 助教授 (80201242)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | transgenicmouse / adenovirus / E1A / E1B / PNET / ENU / cyclin D1 / アデノウィルス12型 / E1 / cyclinD1 / EWS / ETS / キメラ遺伝子 / RB / p53 / ヒルシュスプルング病 / 化学発癌 / エチルニトロソウレア |
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| Research Abstract |
Fused genes of the human renin promoter and adenovirus type 12 E1A-E1B were introduced to C57BL/6J mice to produce transgenic (TG) mice. Eighty-seven percent of TG mice developed tumors, all of which were PNETs. More than half of the TG mice had PNETs from 21 to 40 weeks of age. Before 20 weeks of age, PNETs developed predominantly in the abdomen, pelvic region, trunk, and extremities and the tumor histology was the undifferentiated subtype. In contrast, after 21 weeks of age, PNETs occurred most frequently in the brain and the parameningeal region. PNETs arising in the intracranial and parameningeal regions were medullo-ependymoblastomas or central PNETs which had clear ependymal rosettes. Adenovirus E1A protein binds to the cellular pRB, which cripples a vital cellular growth-suppression mechanism and leads the cell into malignant transformation. E1B gene product binds p53 and inhibits the transcriptional regulatory functions of p53. There was a report that ethylnitrosourea (ENU) adm
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inistration to p53-heterozygous pregnant mice resulted in development of glioblastoma. We assessed the modification effect of ENU with tumorigenesis in our TG mice but revealed no significant differences between ENU-treated and non-treated TG mice. Glioblastoma was not developed. The function of p53 in our TG mice, therefore, was not inhibited by ENU administration and PNET development was independent from the transplacental exposure to ENU.We analysed gene expression levels of cyclin D1 and p21 with PNET developed in the TG mice using real time quantitative RT-PCR method. Gene expression of cyclin D1 was severely repressed in the PNET.The result indicated that high expression of E1A blocked the pRB function in the PNET and p16-cyclinD1-pRB-mediated signal pathway could not be operated anymore just because of the mutation of pRB.PNET occurring in TG mice showed molecular genetical difference from human PNET/Ewing sarcoma. In our TG mice, however, it appeared that co-activation and stable expression of the E1A and E1B transgenes in neuroepithelial cell abolished the tumor-suppressor function of p53 and pRB.The consequences of it could be abnormal DNA replication control or loss of coordination between DNA replication and cell-cycle progression. And both could lead to genome instability, a characteristic of tumor cells. Less
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