TSC2 tumor suppressor protein in cell energy response

描述(申请人提供)：结节性硬化症(TSC)是一种遗传性疾病，其特征是在各种组织中形成错构瘤。TSC1或TSC2抑癌基因的突变是导致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复合体作用于哺乳动物雷帕霉素靶标(MTOR)的上游，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。蛋白质的合成受多种细胞内和细胞外信号的调节，如有丝分裂生长因子、营养充足和细胞能量水平。细胞能量饥饿导致蛋白质合成和细胞生长受到抑制。然而，协调细胞能量水平和细胞生长的分子机制还不是很清楚。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方面发挥着重要作用。本研究的主要目的是研究TSC2在细胞能量反应中的作用和调控。这一提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，并将提供一种令人兴奋的机制，说明如何在分子水平上整合多种信号通路。该项目的结果将揭示Wnt途径失控导致肿瘤发生的分子基础。将实现以下具体目标。 1.确定GSK3和Wnt在TSC-mTOR-S6K通路中的作用。 2.确定AMPK和GSK3在能量饥饿条件下是否协同磷酸化和调节TSC2。 3.阐明AMPK和GSK3磷酸化TSC2在细胞能量反应中的生理作用。 4.探讨TSC2在能量饥饿诱导的细胞死亡中的作用机制。

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.