TSC2 tumor suppressor protein in cell energy response

描述（由申请人提供）：结节性硬化症（TSC）是一种遗传性疾病，其特征是在多种组织中形成错构瘤。TSC1或TSC2肿瘤抑制基因突变是导致TSC的原因。TSC1和TSC2通过控制蛋白质合成，在调节细胞生长和细胞大小方面发挥重要作用。TSC1/TSC2复合物在哺乳动物雷帕霉素靶蛋白（mTOR）上游发挥作用并抑制mTOR功能。这些观察结果表明，TSC1/TSC2是细胞生长和肿瘤形成的关键调节因子。蛋白质合成受多种细胞内和细胞外信号调控，如有丝分裂生长因子、营养充足性和细胞能量水平。细胞能量饥饿导致蛋白质合成和细胞生长的抑制。然而，协调细胞能量水平和细胞生长的分子机制尚不清楚。我们实验室最近的研究表明，TSC2在协调细胞能量水平和细胞生长中起着重要作用。本课题的主要目的是研究TSC2在细胞能量反应中的功能和调控。这一建议的完成将解决细胞生长和细胞能量水平之间协调的基本细胞生物学问题，并将提供多种信号通路如何在分子水平上整合的令人兴奋的机制。这个项目的结果将揭示由Wnt通路失调诱导的肿瘤发生的分子基础。将讨论以下具体目标。

DESCRIPTION (provided by applicant): 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.