Eker rats are susceptible to spontaneous and carcinogen-induced renal cell carcinoma (RCC) due to a germline defect in the tuberous sclerosis 2 (TSC-2) tumor suppressor gene. These animals serve as useful models for studying mechanisms of renal carcinogenesis and the role of the TSC-2 gene in this process. While it is well established that loss of TSC-2 gene function contributes to tumor development in rodents and humans, the normal function(s) of tuberin, the product of the TSC-2 gene, and the mechanism by which loss of function contributes to tumorigenesis are not clear. Recently, data have emerged implicating tuberin as a negative regulator of signaling downstream of AKT. In this renewal application, we will test the hypothesis that tuberin is itself a target for AKT phosphorylation, and that this phosphorylation in conjunction with a PDZ binding domain at tuberin's carboxy terminus regulates tuberin's binding partners, subcellular localization and function within the cell.
In Specific Aim 1 we will test the hypothesis that tuberin is a target for AKT phosphorylation.
In Specific Aim 2 we will identify tuberin binding partners with the potential to exercise spatial control of tuberin function.
In Specific Aim 3 we will determine the functional consequences of tuberin interaction with 14- 3-3 or its PDZ binding partner nNOS on cell signaling downstream of AKT, RHO-mediated cell adhesion and nNOS activity. Studies such as these on the normal function of tuberin have the potential to reveal new interactions between tuberin and cell signaling pathways that can yield valuable information regarding how the TSC-2 suppressor gene participates in renal carcinogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemical Pathology Study Section (CPA)
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Mietz, Judy
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
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United States
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Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39
Alexander, Angela; Cai, Sheng-Li; Kim, Jinhee et al. (2010) ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A 107:4153-8
Alexander, Angela; Kim, Jinhee; Walker, Cheryl L (2010) ATM engages the TSC2/mTORC1 signaling node to regulate autophagy. Autophagy 6:672-3
Kim, Jinhee; Jonasch, Eric; Alexander, Angela et al. (2009) Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res 15:81-90
Short, John D; Houston, Kevin D; Dere, Ruhee et al. (2008) AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27. Cancer Res 68:6496-506
Lu, Karen H; Wu, Weiguo; Dave, Bhuvanesh et al. (2008) Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res 14:2543-50
Woodruff, Teresa K; Walker, Cheryl Lyn (2008) Fetal and early postnatal environmental exposures and reproductive health effects in the female. Fertil Steril 89:e47-51
Hall, William C; Elder, Bruce; Walker, Cheryl Lyn et al. (2007) Spontaneous renal tubular hyperplastic and neoplastic lesions in three Sprague-Dawley rats from a 90-day toxicity study. Toxicol Pathol 35:233-41
Liang, Jiyong; Shao, Shan H; Xu, Zhi-Xiang et al. (2007) The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9:218-24
Cai, Sheng-Li; Tee, Andrew R; Short, John D et al. (2006) Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J Cell Biol 173:279-89

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