Enhancing mTOR-targeted cancer therapy

描述(申请人提供)：泛素蛋白酶体介导的蛋白质降解是一个重要的过程，通过调节许多重要的细胞过程来维持细胞的动态平衡，包括分化、增殖和凋亡。因此，通过这个系统的异常蛋白质降解是包括癌症在内的许多疾病的基础。哺乳动物靶标雷帕霉素(MTOR)分别与Raptor和Rictor结合形成mTOR复合体1(MTORC1)和mTORC复合体2(MTORC2)，在细胞增殖和存活的调节中发挥关键作用。因此，包括传统的雷帕霉素及其类似物(雷帕洛格)和新型mTOR激酶抑制剂在内的mTOR抑制剂要么是被批准用于癌症治疗的药物，要么是在临床试验中被广泛测试的药物。我们和其他人认为mTOR、Raptor和Rictor可以通过涉及E3泛素连接酶FBXW7(也称为FBW7或CDC4)的机制来降解。然而，它们降解的机制以及降解介导的mTOR轴调节对mTOR靶向癌症治疗的影响在很大程度上是未知的。在这一建议中，我们假设mTOR复合体中的关键成分Rictor和Raptor经历了FBXW7介导和GSK3依赖的降解。因此，mTORC1和mTORC2都受降解机制的调节。这一假说将通过实现三个目标来验证：1)证实FBXW7介导的Raptor和Rictor的泛素化和蛋白酶体降解及其对mTOR信号的影响；2)确定GSK3参与FBXW7介导的Rictor和Raptor的降解；以及3)评估mTOR轴的降解调节对mTOR靶向癌症治疗的影响。这项建议的目的是了解Raptor和Rictor被降解的机制，并确定调节这些蛋白质的降解对mTOR靶向癌症治疗的影响。

DESCRIPTION (provided by applicant): Ubiquitin proteasome-mediated protein degradation is an important process in maintaining cellular homeostasis through regulation of many important cellular processes, including differentiation, proliferation and apoptosis. Accordingly, aberrant protein degradation through this system underlies many diseases, including cancer. The mammalian target of rapamycin (mTOR), coupled with raptor and rictor to form mTOR complex 1 (mTORC1) and mTORC complex 2 (mTORC2), respectively, plays a critical role in the regulation of cell proliferation and survival. Hence, mTOR inhibitors including the conventional rapamycin and its analogues (rapalogs) and novel mTOR kinase inhibitors are either approved drugs for cancer therapy or being widely tested in clinical trials. We and other have suggested that mTOR, raptor and rictor can be degraded through a mechanism involving the E3 ubiquitin ligase FBXW7 (also called FBW7 or CDC4). However, the mechanisms underlying their degradation and the impact of degradation-mediated regulation of the mTOR axis on mTOR- targeted cancer therapy are largely unknown. In this proposal, we hypothesize that the key components in the mTOR complexes, rictor and raptor, are subjected to FBXW7-mediated and GSK3-dependent degradation. As a result, both mTORC1 and mTORC2 are regulated by the degradation mechanism. This hypothesis will be tested by accomplishing 3 aims: 1) to demonstrate FBXW7-mediated ubiquitination and proteasome degradation of raptor and rictor and its impact on the mTOR signaling; 2) to determine the involvement of GSK3 in FBXW7-mediated degradation of rictor and raptor; and 3) to evaluate the impact of degradation regulation of the mTOR axis on mTOR-targeted cancer therapy. The objectives of this proposal are to understand the mechanisms through which raptor and rictor are degraded and to determine the impact of regulation of the degradation of these proteins on mTOR-targeted cancer therapy.