Search for New Therapeutic Targets: Using Yeast to Find the GEF for Rheb

摘要

The Tsc1/2 complex known as Hamartin/Tuberin is mutated in the human disease Tuberous Sclerosis and such mutation predisposes for cancer. Tsc1/2 complex has a clearly established chemical release a GTPase Activating Protein or GAP for the small GTPase Rheb. Rheb in turn regulates TOP. The Tor kinases and associated proteins are large complex units that integrate signals pertaining to nutrients and proliferation potential. Tor promotes growth and proliferation and thus de-regulation of Tor is implicated in carcinogenesis and disease. We have worked toward development of a simple genetically tractable model system for understanding of the Tsc1/2 pathway. Our particular interest is in finding factors that work in opposition to Tsc1/2. Typical GTPases such as the Tsc1/2 target Rheb are controlled by both negative regulators (GAPS) and positive regulators known as guanine nucleotide exchange factors or GEFS. Our most important progress has been to establish functional screens for GEF type activators of the Rheb signalling factor in the simple yeast Schizosaccharomyces pombe.