| Budget Amount *help |
¥10,200,000 (Direct Cost: ¥10,200,000)
Fiscal Year 2000: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1999: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Research Abstract |
To investigate whether loss of p53 contributes to brain tumor induction, we used p53-deficient mice to establish a brain tumor model with ENU exposure during embryonic stages.
ENU administration to p53-heterozygous pregnant mice resulted in rapid development of primary brain tumors, which are extremely rare in mice, in 70% of the p53-null offspring. Brain tumors also developed later in 4% of heterozygous mice, but they had lost the wild-type allele. These results indicate that all the brain tumors in this experiment occur in the p53-null background. To clarify how p53 loss influences brain tumorigenesis in mice, we examined embryo and showed that carcinogen-induced apoptotic cell death is a p53-dependent pathway in specific region and specific developmental stage of embryonal and newborn brain.
At the day 12.5 of gestation, transplacental exposure of ENU showed apoptosis in the cerebral hemisphere in the wild and, to the lesser extent, heterozygous embryos, but not in the p53 null embryos. The region showing apoptosis in the wild type brain was consistent with the sites of glial tumor development in the p53 null mice. Furthermore, BrdU labeling demonstrated that the region showed marked proliferative activity at this developmental stage.
To confirm the findings that p53-dependent apoptosis and proliferative activity are necessary to develop the brain tumor, we examined ENU administration to the new born mice. At 5 days after birth, ENU injection demonstrated p53-dependent apoptosis in the external granular layer of the cerebellum. BrdU labeling also showed proliferative activity in this area. Furthermore, medulloblastomas developed from the cerebellum 3 month after ENU injection.
Taken together, these results demonstrate that p53 play a critical role in eliminating carcinogen-induced damaged cells with proliferative activity via an apoptotic pathway in the developing mouse brain, thus inhibiting brain tumorigenesis.
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