Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that affects about 1 in 6000 individuals. It is characterized by occurrence of various benign tumors, often classified as hamartomas, in multiple organs, including brain, kidney, heart, lung, and skin. Despite their benign nature, the lesions of TSC often led to severe neurological disorder and organ failure, causing morbidity and mortality in affected individuals. Genetic mutations associated with TSC have been mapped to two separated loci, TSC1 and TSC2. The gene products of TSC1 and TSC2, hamartin and tuberin, form a complex that negatively regulates Rheb, a Ras-like small GTP binding protein. It has been recently found that mTOR, the target of rapamycin, is a major effector of Rheb. As a central regulator of cell growth, mTOR acts by integrating signals initiated by changes in growth factor and nutrient conditions. The connection between the TSC-Rheb pathway and mTOR signaling provides an effective explanation for the role of the TSC1/TSC2 complex in cell growth control and their dysfunction in tumorigenesis. Despite the recent advances, two critical questions remain unanswered in our understanding of pathogenic mechanisms underlying TSC. First, how does Rheb regulate mTOR? Second, is mTOR the only mediator that contributes to tumorigenesis associated with TSC deficiency? In an attempt to answer these questions, we have identified a novel mechanism that bridges the TSC-Rheb pathway to mTOR signaling and apoptosis. This exciting finding promotes us to hypothesize that Tsc deficiency promotes tumorigenesis by stimulating mTOR signaling and preventing apoptosis. In this research plan, we will investigate the molecular basis by which the TSC-Rheb pathway controls these two important processes in cell growth and proliferation. The long term goal of this research plan is to define the molecular basis underlying the tumorigenesis associated with TSC deficiency. Successful completion of this research plan will help to understand the tuberous sclerosis complex and provide molecular basis for developing therapeutic agents to treat and prevent this devastating disease. PUBLIC HEALTH RELVANCE: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder that is manifested by occurrence of benign tumors in multiple organs. The disease condition is caused by inactivating mutations in either the TSC1 or TSC2 tumor suppressor gene. However, how dysfunction in the two tumor suppressor genes leads to tumorigenesis in animal and human is poorly understood. We have evidence suggest that the tumorigenesis associated with TSC may be caused by an imbalance between cell proliferation and death, owing to defects in the TSC1 and TSC2 genes. In this proposal, we plan to study a novel signal transduction mechanism by which the two tumor suppressors controls both cell growth and death. Successful completion of this study would allow us to identify potential therapeutic target for intervention of the tuberous sclerosis complex and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129821-05
Application #
8212092
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2008-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$274,439
Indirect Cost
$93,291
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wang, Juan; Menon, Shekar; Yamasaki, Akinori et al. (2013) Ypt1 recruits the Atg1 kinase to the preautophagosomal structure. Proc Natl Acad Sci U S A 110:9800-5
Zou, Huafei; Lai, Yumei; Zhao, Xuwen et al. (2013) Regulation of mammalian target of rapamycin complex 1 by Bcl-2 and Bcl-XL proteins. J Biol Chem 288:28824-30
Yan, Gonghong; Lai, Yumei; Jiang, Yu (2012) The TOR complex 1 is a direct target of Rho1 GTPase. Mol Cell 45:743-53
Yoon, Mee-Sup; Sun, Yuting; Arauz, Edwin et al. (2011) Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. J Biol Chem 286:29568-74
Bai, Xiaochun; Jiang, Yu (2010) Key factors in mTOR regulation. Cell Mol Life Sci 67:239-53
Ma, Dongzhu; Bai, Xiaochun; Zou, Huafei et al. (2010) Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL. J Biol Chem 285:8621-7
Cao, Huiling; Yu, Shibing; Yao, Zhi et al. (2010) Activating transcription factor 4 regulates osteoclast differentiation in mice. J Clin Invest 120:2755-66
Ma, Dongzhu; Bai, Xiaochun; Guo, Shuguang et al. (2008) The switch I region of Rheb is critical for its interaction with FKBP38. J Biol Chem 283:25963-70