| 概要： |
Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome that leads to benign tumor development in several organs, including the brain, lungs, heart, kidneys, and skin, and is due to inactivating mutations in either of TSC1 or TSC2. Following our discovery of the TSC1 gene a decade ago, the TSC1 and TSC2 gene products were shown to form a tight binding complex, and then shown to play a critical role in an ancestrally conserved signaling pathway to regulate the activity of the mTORC1 complex to regulate both cell size and cell growth. Our recent studies have focused on three aspects of TSC, TSC1, and TSC2.
First, we have identified a feedback pathway that limits Akt activation when the TSC1/TSC2 complex is inactivated. TSC1/TSC2 functions as a GTPase activating protein (GAP) for Rheb, which functions in its GTP-bound state to activate the mTORC1 complex. Loss of TSC1/TSC2 leads to high levels of Rheb-GTP and constitutive activation of mTORC1. This leads to several different feedback effects which limit Akt activation. We identified reduction in expression of the PDGFRs as one important mechanism of this effect, and have shown that it occurs at the transcriptional level. Reduced PDGFR expression occurs whenever mTORC1 is chronically activated, and this effect is reversed by rapamycin treatment. The reduced PDGFR expression also impairs signaling from EGF, IGF, and PMA to Akt. Over-expression of PDGFR rescues this feedback effect and markedly enhances the tumorigenicity of Tsc2 null fibroblasts (MEFs), suggesting that this feedback effect contributes to the lack of cancer seen in TSC patients.
Second, we have shown that rapamycin is an effective therapeutic agent in the treatment of kidney and liver tumors that develop in TSC mouse models. Chronic long-term (9 months) treatment with rapamycin (4mg/kg IP 3x/wk) suppresses 95% of tumor development in Tsc1+- mice. Shorter term treatment is also very effective in causing tumor regression with conversion of solid adenomas to residual cysts, and reduced proliferation. In addition, we have recently explored the possibility that statin therapy, through blockade of HMG-CoA reductase, could block isoprenylation to inhibit G protein activity in cells lacking Tsc1/Tsc2. Atorvastatin has selective growth effects on Tsc1/Tsc2 null MEFs, reduces the isoprenylation and membrane localization of Rheb, and inhibits mTORC1 activation. Therapeutic trials of atorvastatin in Tsc mouse models are underway.
Third, we have developed a mouse TSC brain model. We used a SynICre allele combined with our Tsc1c allele to induce recombination and loss of Tsc1 during neuronal development. Tsc1c-SynICre+ mice have a median survival of 32 days, with tremulousness, an enhanced startle response, and tendency for fatal seizures. Many cortical and hippocampal neurons are enlarged and/or dysplastic in this Tsc1 neuronal model, strongly express phospho-S6, and are ectopic in multiple sites in the cortex and hippocampus. There is a striking delay in myelination in the mutant mice, which appears to be due to an inductive neuronal defect. Thus, this model replicates several features of human TSC brain lesions, and implicates an important function of Tsc1/Tsc2 in neuronal development. Finally, rapamycin therapy initiated at post-natal day 8 is dramatically effective in this model with over 90% of mutant mice surviving over 100 days.
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