Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with mutations in two different genes, TSC1 and TSC2, which cause the widespread of benign tumors called hamartomas. These tumors are found in different organs including the brain, eyes, heart, kidney, skin, and lungs. Seizures and learning and behavioral problems, which are due to development of tumors in brain, are also common in patients with TSC. There is no effective cure for TSC; treatment is symptomatic and includes anticonvulsant therapy for seizures, drug therapy for neurobehavioral problems, treatment of high blood pressure caused by kidney dysfunction, and surgery to remove growing tumors. Because hamartomas could be distributed at multiple sites throughout the body, an ideal treatment would be the use of a drug that can specifically suppress the growth of hamartomas.

Recent studies have revealed that TSC1/2 gene products control cell growth/proliferation in response to growth factors and available nutrients. A biochemical function of the two gene products is to inactivate a GTPase, RHEB. An active RHEB in turn stimulates mTOR, a kinase, which induces protein synthesis, so it is speculated that RHEB is continuously active and stimulates mTOR for cell growth/proliferation in cells lacking functional TSC1 or TSC2. Hamartomas in patients with TSC are, at least in part, thereby attributable to abnormal activation of RHEB and its target mTOR. A chemical compound called rapamycin is an inhibitor of mTOR and is currently considered to be a drug for treatment of TSC. If hamartomas are caused solely due to abnormal activation of mTOR via RHEB, rapamycin may be an effective drug to cope with TSC. On the other hand, if TSC1/2 gene products regulate a yet unidentified element in addition to RHEB and mTOR, the efficacy of rapamycin is probably limited.

TSC1 and TSC2 gene products are evolutionarily conserved from human to a simple and tractable organism, fission yeast. We previously showed that yeast cells lacking either TSC1 or TSC2 cannot sense a shortage of nutrients. As a result, genes normally induced upon starvation are not induced. Also, a protein that is positioned on the cell surface in starving cells is confined inside. In this proposal we take advantage of classical and modern genetics available in the fission yeast model system and address the following two questions: (1) Are all the defects found in yeast cells lacking TSC1 or TSC2 due to continuous activation of RHEB? To address this question, we genetically manipulate the fission yeast RHEB and allow continuous activation RHEB even when TSC1 and TSC2 are functional. The consequence of the continuous activation of RHEB will be compared to that of loss of TSC1 or TSC2. (2) To what else does TSC1/2 "talk" in addition to RHEB? To address this question, we will perform genomewide screens for genes whose upregulation or downregulation can offset lack of TSC1 or TSC2.

The results from the fission yeast model study would allow not only prediction of the efficacy of rapamycin for TSC, but also identification of novel genes that could be a target of an effective drug to cope with TSC.