Tuberous sclerosis complex (TSC) is a tumor syndrome affecting approximately one in 6,000 individuals, most often in early childhood. This clinically severe disease is caused by mutations in one of two tumor suppressor genes, TSC1 and TSC2, whose gene products form a complex. Recent studies by our laboratory and others have found that this complex is a critical negative regulator of the mammalian target of rapamycin (mTOR). Cells and tumors lacking TSC gene function exhibit constitutive mTOR signaling, and this contributes to tumor formation in mouse models of TSC. In addition, this elevated mTOR activity triggers a negative feedback loop in TSC-deficient cells that renders the PI3K-Akt pathway unresponsive to specific growth factors. The PI3K-Akt pathway is a critical cell survival and proliferation pathway that is aberrantly activated in a large percentage of human cancers. Using mouse genetics, we have recently found that feedback inhibition of this pathway limits the growth of TSC tumors. Our central hypothesis is that Akt attenuation upon loss of TSC gene function significantly affects the survival and proliferation properties of TSC cells and tumors. Additionally, as treatment with the mTOR inhibitor rapamycin, which is currently in clinical trials for TSC, can restore Akt signaling in these cells, we predict that this drug will also enhance the survival of TSC cells. The studies described in this proposal will determine the implications of these defects in Akt signaling with an emphasis on identifying novel therapeutic opportunities for the treatment of TSC.
The specific aims are: 1) characterize defects in Akt-mediated cell survival signaling in Tsc-deficient cells and tumors and the effects on the apoptotic potential of cells lacking the TSC genes; 2) compare the effectiveness of combination therapy inhibiting both mTOR and the PI3K-Akt pathway to mTOR inhibition alone toward inducing apoptosis in TSC cell culture and mouse models; 3) determine the mechanism of regulation of GSK3 in Tsc-deficient cells and its effects on the growth factor-independent proliferation property of these cells; 4) determine if the defects in Akt signaling extend to Tsc-deficient neurons. A detailed molecular understanding of the signaling defects triggered by functional inactivation of the TSC1/2 complex is critical to the design of proper treatments for TSC and to our knowledge of the wide variety of human diseases, such as sporadic cancers and diabetes, in which this pathway is involved. ? ? ?
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