TSC2 tumor suppressor protein in cell energy response

细胞能量反应中的 TSC2 肿瘤抑制蛋白

• 批准号: 6946505
• 负责人: Kun-Liang Guan
• 金额: $ 32.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-03 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946505
• 关键词: adenosine triphosphate; apoptosis; bioenergetics; biological signal transduction; biosynthesis; biotransformation; carcinogenesis; cell growth regulation; cell proliferation; flow cytometry; gene mutation; neoplasm /cancer genetics; neoplastic process; phosphorylation; protein biosynthesis; tuberous sclerosis; tumor suppressor genes; tumor suppressor proteins

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.

描述（由申请人提供）：结节性硬化症复合物（TSC）是一种遗传疾病，其特征是在各种组织中形成Hamartoma。 TSC1或TSC2肿瘤抑制基因中的突变负责TSC。通过控制蛋白质合成，TSC1和TSC2在调节细胞生长和细胞大小中起主要作用。 TSC1/TSC2复合物的功能在雷帕霉素（MTOR）的哺乳动物靶标上游并抑制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剂。蛋白质合成受多个细胞内和细胞外信号的调节，例如有丝分裂生长因子，养分充足和细胞能量水平。细胞能量饥饿会导致抑制蛋白质合成和细胞生长。然而，尚不清楚协调细胞能级和细胞生长的分子机制。我们实验室的最新研究表明，TSC2在协调细胞能量水平和细胞生长中起着重要作用。该提案的主要目的是研究TSC2在细胞能量反应中的功能和调节。该提案的完成将解决细胞生长和细胞能级之间协调的基本细胞生物学问题，并将提供令人兴奋的机制，说明如何在分子水平整合多个信号通路。该项目的结果将揭示因疏离Wnt途径引起的肿瘤发生的分子基础。将解决以下特定目标。 1。确定在TSC-MTOR-S6K途径中GSK3和WNT的功能。 2。确定在能量饥饿条件下，AMPK和GSK3是否合作磷酸化并调节TSC2。 3。阐明AMPK和GSK3在细胞能量反应中通过AMPK和GSK3磷酸化的生理功能。 4。研究能量饥饿诱导的细胞死亡中TSC2的机理。