Tuberous sclerosis is a clinical disorder whose manifestations include both benign and malignant diseases. The mechanism of their pathogenesis is not known but the identification of one of the genes responsible for this autosomal dominant syndrome, TSC2, has provided an avenue to investigate the molecular basis of this complex syndrome. TSC2 is a novel gene that encodes about 190kD membrane bound protein, known as tuberin, that has limited homology with the catalytic domain of rap1GAP. Although biochemical studies have demonstrated specific in vitro GTPase activating function for rap1a, how this GAP activity relates to its physiologic function and the pathways in which it causes cancer, development remains to be elucidated. Our approach to study these questions exploits the use of a unique animal model, the Eker rat, that carries a germline mutation of this gene. Although initially described as a model of hereditary cancer, closer examination revealed striking phenotypic parallels between the human disorder and the Eker rat. As such, it can serve as an animal model of tuberous sclerosis. Molecular, genetic and cell biologic analyses of our animal model have provided the strongest evidence to date that TSC2 behaves as a tumor suppressor gene. In this proposal, our aim is to elucidate the signaling pathway(s) that is relevant to tuberin tumor suppressor function and to understand the biochemical basis of TSC2- related disorders. Specifically, the studies will propose 1) to identify and characterize proteins that interact with tuberin, 2) to analyze the function of these tuberin-binding proteins in the context of cellular transformation, and 3) to assess the role of TSC2-GAP function in tumorigenesis. Creating this network of information about tuberin and its interacting proteins will facilitate our long-term objective of identifying therapeutic targets that will benefit those who suffer from these devastating diseases.
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