Tuberous sclerosis complex (TSC) is a genetic disease characterized by hamartoma formations in a wide range of tissues. Mutation in either the TSC1 or TSC2 tumor suppressor gene is responsible for TSC. TSC1 and TSC2 play a major role in the regulation of cell growth and cell size through control of protein synthesis. The TSC1/TSC2 complex functions upstream of the mammalian target of rapamycin (mTOR) and inhibits mTOR function. These observations suggest that TSC1/TSC2 are key regulators of cell growth and tumor formation. Protein synthesis is regulated by multiple intracellular and extracellular signals, such as mitogenic growth factors, nutrient sufficiency, and cellular energy levels. Cellular energy starvation results in inhibition of both protein synthesis and cell growth. However, the molecular mechanisms coordinating cellular energy level and cell growth is not well understood. Recent studies from our laboratory have indicated that TSC2 plays a major role in coordinating cellular energy levels and cell growth. The major goal of this proposal is to study the function and regulation of TSC2 in the cellular energy response. Completion of this proposal will address the fundamental cell biology question of the coordination between cell growth and cellular energy levels and will provide an exciting mechanism of how multiple signaling pathways are integrated at the molecular level. Results from this project will reveal a molecular basis for tumorigenesis induced by disregulation of the Wnt pathway. The following specific aims will be addressed. 1. To determine the function of GSK3 and Wnt in the TSC-mTOR-S6K pathway. 2. To determine whether AMPK and GSK3 collaboratively phosphorylate and regulate TSC2 under energy starvation conditions. 3. To elucidate the physiological functions of TSC2 phosphorylation by AMPK and GSK3 in cellular energy response. 4. To investigate the mechanism of TSC2 in energy starvation-induced cell death.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108941-04
Application #
7240561
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
2004-09-03
Project End
2007-09-30
Budget Start
2007-07-01
Budget End
2007-09-30
Support Year
4
Fiscal Year
2007
Total Cost
$73,525
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Qian; Meng, Fansen; Chen, Shasha et al. (2017) Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 19:362-374
Plouffe, Steven W; Hong, Audrey W; Guan, Kun-Liang (2015) Disease implications of the Hippo/YAP pathway. Trends Mol Med 21:212-22
Wang, Pu; Wu, Jing; Ma, Shenghong et al. (2015) Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep 13:2353-2361
Zha, Zhengyu; Han, Xiaoran; Smith, Matthew D et al. (2015) A Non-Canonical Function of G? as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation. Mol Cell 58:794-803
Jewell, Jenna L; Flores, Fabian; Guan, Kun-Liang (2015) Micro(RNA) managing by mTORC1. Mol Cell 57:575-576
Yuan, Hai-Xin; Guan, Kun-Liang (2015) The SIN1-PH Domain Connects mTORC2 to PI3K. Cancer Discov 5:1127-9
Hansen, Carsten Gram; Ng, Yuen Lam Dora; Lam, Wai-Ling Macrina et al. (2015) The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1. Cell Res 25:1299-313
Kim, Young Chul; Guan, Kun-Liang (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 125:25-32
Yang, Hui; Zhou, Lisha; Shi, Qian et al. (2015) SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J 34:1110-25
Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163:811-28

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