Enhancing mTOR-targeted cancer therapy

描述（由申请人提供）：泛素蛋白酶体介导的蛋白质降解是维持细胞稳态的重要过程，通过调节许多重要的细胞过程，包括分化、增殖和凋亡。因此，通过该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rapamycin靶点（mTOR）分别与raptor和rictor偶联形成mTOR复合物1 （mTORC1）和mTORC复合物2 (mTORC2)，在细胞增殖和存活调控中起关键作用。因此，mTOR抑制剂，包括传统的雷帕霉素及其类似物（rapalogs）和新型mTOR激酶抑制剂，要么被批准用于癌症治疗，要么在临床试验中广泛测试。我们和其他人已经提出mTOR、raptor和rictor可以通过E3泛素连接酶FBXW7（也称为FBW7或CDC4）的机制被降解。然而，它们降解的机制以及降解介导的mTOR轴调控对mTOR靶向癌症治疗的影响在很大程度上是未知的。在这项提议中，我们假设mTOR复合物中的关键组分，rictor和raptor，受到fbxw7介导和gsk3依赖的降解。因此，mTORC1和mTORC2都受到降解机制的调节。这一假设将通过实现3个目标来验证：1)证明fbxw7介导的raptor和rictor的泛素化和蛋白酶体降解及其对mTOR信号传导的影响；2)确定GSK3参与fbxw7介导的vector和raptor的降解；3)评价mTOR轴降解调控对mTOR靶向癌症治疗的影响。本提案的目的是了解raptor和rictor降解的机制，并确定这些蛋白质降解的调节对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. PUBLIC HEALTH RELEVANCE: The objectives of the 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. Thus, this proposal not only helps us to understand the biology of mTOR regulation by degradation, but also has great translational significance that immediately impacts clinical treatment of cancer.