A Genetic Approach to Define the Importance of Rheb in Tuberous Sclerosis

Principal Investigator: TAMANOI, FUYUHIKO
Program: TSCRP
Proposal Number: TS043015
Award Number: W81XWH-05-1-0164
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $411,672.00


Tuberous sclerosis (TSC) is an autosomal-dominant disorder characterized by mutations in the TSC1 or TSC2 genes with pathological consequences in the heart, lung, and kidneys, as well as mental retardation, epilepsy, and autism. Many features of the disease are caused by benign tumors called hamartomas. In rare cases, hamartomas progress to malignant carcinomas. Previous studies have established that the TSC1 and TSC2 proteins form a complex and that this TSC1/TSC2 complex is a major component of an important insulin-regulated pathway called the insulin/mTOR/S6K-signaling pathway. That pathway regulates cell growth and cell cycle progression. Recently, we as well as others have identified a direct target of the TSC1/TSC2 protein complex. The target, Rheb, is a novel protein that binds GTP and has the ability to activate mTOR and subsequently S6K. A current working model for the function of the TSC1/TSC2 complex postulates that this complex inhibits the activity of Rheb. The consequence of Rheb inhibition is a downregulation of mTOR/S6K activity and a decrease in cell growth and proliferation.

The identification of Rheb as a target of the TSC1/TSC2 complex is an exciting development in the study of TSC, as it suggests that overactive Rheb signaling may contribute to the development of tuberous sclerosis. This is highly significant from a therapeutic perspective: Rheb may be a potential target for drugs aimed at reducing the development of tumors in tuberous sclerosis patients.

We will use genetically modified mice to define interactions between Rheb and Tsc. Tsc-knockout mice have been shown to exhibit phenotypes such as an increased incidence of tumors (carcinomas of the kidney in particular). We plan to determine if the inhibition of Rheb suppresses these Tsc phenotypes. Toward this goal, we have recently succeeded in generating mice in which one of the Rheb genes, Rheb1, has been knocked out. Experiments to inactivate a second Rheb gene, Rheb2, are ongoing. These knockout mice will be investigated. We will then cross the Rheb-knockout mice with Tsc-knockout mice to investigate the effects of Rheb inhibition on the Tsc phenotypes.

The results obtained from this study will have significant implications for the understanding of the pathology of tuberous sclerosis. As noted previously, Rheb may emerge as a critical therapeutic target for treating tuberous sclerosis. In addition, the availability of Rheb-knockout mice as well as Rheb-deficient Tsc-knockout mice will provide valuable reagents for studying the pathogenesis of tuberous sclerosis and the function of the Tsc genes.