The mTOR and Hippo pathway in cell growth and cancer

mTOR 和 Hippo 通路在细胞生长和癌症中的作用

• 批准号: 9120339
• 负责人: Kun-Liang Guan
• 金额: $ 91.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120339
• 关键词: Amino Acids; Amino Acids Activation; Anabolism; Apoptosis; Autophagocytosis; Biochemical; Cancer Cell Growth; Development; FRAP1 gene; Genetic Transcription; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Homeostasis; Human; Malignant Neoplasms; Mediator of activation protein; Mission; Molecular; Nature; Organ; Organ Size; Pathway interactions; Pharmaceutical Preparations; Physiological; Proto-Oncogene Proteins c-akt; Regulation; Signal Pathway; Signal Transduction; Stimulus; Tissues; Tumor Suppressor Proteins; Work; base; cancer therapy; cell growth; cell growth regulation; design; inhibitor/antagonist; organ growth; sensor; tumorigenesis

 DESCRIPTION (provided by applicant): Understanding the basic mechanisms of cell growth regulation and how alteration of such regulatory networks leads to cancer is fundamentally important for understanding cancer development and designing new strategies for treating cancer. The mTORC1 and Hippo signaling pathways are two major pathways that control cell growth and tissue/organ homeostasis. mTORC1 is a central cell growth controller which promotes cell growth by stimulating biosynthesis and inhibiting autophagy. The Hippo tumor suppressor pathway limits tissue and organ size by inhibiting proliferation and stimulating apoptosis. Dysregulation of either pathway contributes to human cancer. As such, mTORC1 inhibitors have received FDA approval for cancer treatment and there is an intensive effort in searching for drugs that can target the Hippo pathway for cancer indication. Previous works from the PI have revealed the molecular mechanisms of mTORC1 regulation by growth factors and cellular energy status via AKT and AMPK, respectively. Amino acids are arguably the most important stimuli of mTORC1. The PI has also identified Rag GTPases as critical mediators of mTORC1 activation by amino acids. Despite rapid progress in the field, key issues in amino acid signaling to mTORC1, such as the nature of amino acid sensors, remain to be solved. One major goal of this R35 proposal is to elucidate the molecular mechanism of mTORC1 activation by amino acids. The Hippo pathway is an exciting emerging field. The PI's group has made key contributions in establishing the major framework of the Hippo pathway, including identification of upstream signals, the biochemical mechanism of YAP regulation, and demonstration of the YAP-TEAD transcription module. However, fundamental issues such as regulation of core Hippo pathway components, molecular basis of YAP in promoting oncogenesis, and physiological signals that control organ size are key open questions that have yet to be answered. The overall mission of this R35 proposal is to obtain a comprehensive molecular understanding of the mTORC1 and Hippo pathways under normal physiological conditions and to elucidate how dysregulation of these pathways contributes to tumorigenesis.

 描述（适用提供）：了解细胞生长调节的基本机制以及这种调节网络的改变如何导致癌症对于理解癌症发展和设计治疗癌症的新策略至关重要。 MTORC1和HIPPO信号通路是控制细胞生长和组织/器官稳态的两个主要途径。 MTORC1是一种中央细胞生长控制器，通过刺激生物合成和抑制自噬来促进细胞生长。河马肿瘤抑制途径通过抑制增殖和刺激凋亡来限制组织和器官的大小。这两种途径的失调都会导致人类癌症。因此，MTORC1抑制剂已获得FDA批准用于癌症治疗，并且在寻找可以针对河马途径的癌症指示的药物方面做出了强烈的努力。 PI的先前工作揭示了通过AKT和AMPK分别通过生长因子和细胞能状态调节MTORC1调控的分子机制。氨基酸可以说是MTORC1最重要的刺激。 PI还确定了抹布GTPases是氨基酸激活MTORC1激活的关键介体。尽管该领域的进展很快，但氨基酸信号传导的关键问题（例如氨基酸传感器的性质）仍有待解决。该R35建议的主要目标是阐明氨基酸MTORC1激活的分子机制。河马途径是一个令人兴奋的新兴领域。 PI的组在建立河马途径的主要框架方面做出了关键贡献，包括识别上游信号，YAP调节的生化机制以及YAP-TEAD转录模块的演示。但是，诸如核心河马途径成分的调节，促进肿瘤发生的分子基础等基本问题以及控制器官大小的物理信号是尚未回答的关键开放问题。该R35提案的总体任务是在正常生理条件下获得对MTORC1和HIPPO途径的全面分子理解，并阐明这些途径的失调如何导致肿瘤发生。