Tuberous sclerosis complex: from Drosophila to human disease.
Tuberous sclerosis complex (TSC) is a human syndrome characterized by a widespread development of benign tumors. This disease is caused by mutations in the TSC1 or TSC2 tumor suppressor genes; the molecular mechanisms underlying the activity of these have long been elusive. Recent studies of Drosophila and mammalian cells demonstrate that the TSC1-TSC2 complex functions as GTPase activating protein against Rheb - a Ras-like small GTPase, which in turn regulates TOR signaling in nutrient-stimulated cell growth. These findings provide a new paradigm for how proteins involved in nutrient sensing could function as tumor suppressors and suggest novel therapeutic targets against TSC. Here, we review these exciting developments with an emphasis on Drosophila studies and discuss how Drosophila can be a powerful model system for an understanding of the molecular mechanisms of the activity of human disease genes.
Pan
Duojia
D
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9040, USA. Duojia.Pan@UTSouthwestern.edu
Dong
Jixin
J
Zhang
Yong
Y
Gao
Xinsheng
X
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D012097:Repressor Proteins; C490212:Rheb protein, Drosophila; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D020794:Receptor Protein-Tyrosine Kinases; C080148:tor protein, Drosophila; D020559:Monomeric GTP-Binding Proteins