| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
Tuberous sclerosis complex (TSC) is caused by a mutation of either the TSC1 or TSC2 gene. The protein product of the TSC2 gene, tuberin, is a negative regulator of the insulin signal transduction pathway. Factors upstream of tuberin include insulin, PI3K and Akt, and those downstream of tuberin include Rheb, mTOR, p70S6K and S6. Previous studies have revealed that, in human TSC lesions (tumors and hamartias) dysfunction of tuberin causes hyper-activation of the mTOR pathway and over-phosphorylation of S6. Tumors occur according to the two-hit hypothesis. The activity of upward factors, such as PI3K and Akt, was hypothesized to be suppressed by a feedback mechanism. In hamartias like cortical tubers of the cerebral cortex, there is no second hit, and the possibility of constitutive activation of the PI3K/Akt pathway has been pointed out.
In this study, we first examined these hypotheses by immunohistochemical studies of Eker rat, an animal model of TSC caused by a loss-of-function mutati
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on of the Tsc2 gene. Malignant tumors of the Eker rat cerebrum and kidneys showed no hyper-activation of Akt. The hyper-phosphorylation of mTOR and p70S6K was noted in a small subpopulation of tumor cells. In the cerebral hamartia (cortical tuber), there was normal Akt phosphorylation, as well as an absence of mTOR and p70S6K phosphorlation, in contrast to hyper-phosphorylation of Akt and p70S6K in reactive astrocytes. All these lesions, both tumors and hamartias, showed prominent hyper-phosphorylation of S6.
We nest examined the phophorylation status of these factors by Western blotting. In the kidneys (non-cancerous tissues) and cerebrum, the expression and phosphorylation of Akt, tuberin, mTOR, p70S6K and S6 was normal. The renal cell cancer of Eker rats showed hypo-phosphorylation of Akt, low expression of tuberin, high expression of mTOR and hyper-phosphorylation of S6, but no hyper-phosphorylation of p70S6K.
These results suggested a negative feedback mechanism from the downstream to the upstream of this pathway, and S6 activation by a factor other than p70S6K. Less
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