Enhancing mTOR-targeted cancer therapy

描述（由申请人提供）：泛素蛋白酶体介导的蛋白降解是通过调节许多重要的细胞过程（包括分化、增殖和凋亡）来维持细胞稳态的重要过程。因此，通过该系统的异常蛋白质降解是许多疾病，包括癌症的基础。哺乳动物雷帕霉素靶蛋白（mTOR）与raptor和rictor偶联，分别形成mTOR复合物1（mTORC 1）和mTORC复合物2（mTORC 2），在细胞增殖和存活的调节中起关键作用。因此，包括常规雷帕霉素及其类似物（rapalogs）和新型mTOR激酶抑制剂在内的mTOR抑制剂是批准用于癌症治疗的药物或在临床试验中被广泛测试。我们和其他人认为mTOR、raptor和rictor可以通过涉及E3泛素连接酶FBXW 7（也称为FBW 7或CDC 4）的机制降解。然而，其降解的潜在机制以及mTOR轴的降解介导的调节对mTOR靶向癌症治疗的影响在很大程度上是未知的。在这个提议中，我们假设mTOR复合物中的关键组分，rictor和raptor，受到FBXW 7介导的和GSK 3依赖性的降解。因此，mTORC 1和mTORC 2均受降解机制调节。该假设将通过实现3个目的进行检验：1）证明FBXW 7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GSK 3参与FBXW 7介导的rictor和raptor降解; 3）评价mTOR轴的降解调节对mTOR靶向癌症治疗的影响。该提案的目的是了解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。 公共卫生相关性：该提案的目的是了解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。因此，这一提议不仅有助于我们理解mTOR通过降解调节的生物学，而且具有巨大的翻译意义，直接影响癌症的临床治疗。

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.