Control of Protein Synthesis by the UPS Under Stress

应激状态下 UPS 对蛋白质合成的控制

基本信息

批准号：
9301496
负责人：
Ze'ev A Ronai
金额：
$ 43.87万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301496
关键词：
Area Attenuated Breast Cancer Cell Breast Cancer cell line Cancer Biology Cellular Stress Cellular Stress Response Collaborations Complement Complex Cullin 2 Protein Cullin Proteins Data Data Set Development ERBB2 gene Growth Individual Link Mediating Mining N-terminal Neoplasm Metastasis Phosphorylation Phosphotransferases Physiological Polyribosomes Progesterone Receptors Protein Biosynthesis Proteins Proteome Recruitment Activity Regulation Research Resolution Ribosomes Role Stress System Technology The Cancer Genome Atlas Time Translating Ubiquitin Ubiquitination Xenograft procedure arm base cell growth cohort erbB-2 Receptor experimental study genetic regulatory protein improved inhibitor/antagonist malignant breast neoplasm multicatalytic endopeptidase complex nanopore nanosensors novel protein degradation receptor expression response treatment response ultraviolet irradiation

项目摘要

PROJECT SUMMARY This proposal is based on a newly discovered regulatory arm of the cellular stress response, whereby Jun N- terminal kinase (JNK) is recruited to translating ribosomes (polysomes) to mediate degradation of newly synthesized proteins (NSPs). We established the significance of this novel regulatory module to breast cancer (BCa) biology, and identify ubiquitin proteasome system (UPS) components that—for the first time—are linked with the surveillance of NSPs. They include Cullin 2, Nedd8, and ubiquilin1 (UBQLN1), which we demonstrate to impact protein synthesis in BCa cells. Dysregulated expression of these UPS components in BCa underlies the rationale for studying their role in BCa development and response to therapy. Our preliminary results support the hypothesis that control of NSP stability constitutes a novel layer of regulation of protein synthesis/availability, which in turn governs cellular responses to stress. We further hypothesize that such regulation has direct implications for BCa development and response to therapy. We focus on several complementary but hitherto unappreciated mechanisms that may underlie NSP surveillance under stress. The productive and long-standing collaborations between Drs. Topisirovic, Sonenberg, Mills and Ronai are now extended to include Dr. Meller, thereby enabling extensive and complementary expertise in the areas of protein synthesis and cancer biology to also include nanopore-sensing technology, enabling the resolution of ubiquitin chain topologies. Together, we will assess specific, newly identified NSP regulatory factors that function individually or in concert to regulate the cellular stress response, particularly in the context of BCa development and response to therapy. The proposed research will: (1) Establish the physiological significance of the RACK1–JNK–eEF1A2 regulatory axis to the cellular stress response, growth and therapeutic response of breast cancer. (2) Assess the role of stress-induced polysomal recruitment of Nedd8–Cullin machinery in regulating the decay of NSPs in BCa. (3) Determine the importance of UBQLN1 recruitment to polysomes in regulating newly synthesized proteins under stress conditions and in modulating the response of BCa to therapy. Our proposed studies will establish the importance and significance of select UPS components in a novel regulatory network that controls protein synthesis during cellular stress, and establish its role in BCa using a combination of BCa cultures and xenografts, RPPA technology, and TCGA dataset mining.

项目概要该提议基于新发现的细胞应激反应调节臂，因此 Jun N- 末端激酶（JNK）被招募来翻译核糖体（多核糖体）以介导新的降解我们确定了这种新型调节模块对乳腺癌的重要性。 (BCa) 生物学，并首次鉴定出相互关联的泛素蛋白酶体系统 (UPS) 组件它们包括 Cullin 2、Nedd8 和 ubiquilin1 (UBQLN1)，我们对此进行了演示。影响 BCa 细胞中这些 UPS 成分表达失调的基础。研究它们在 BCa 发展和治疗反应中的作用的基本原理。我们的初步结果支持这样的假设：NSP 稳定性的控制构成了一个新的层蛋白质合成/可用性的调节，进而控制细胞对压力的反应。此外，此类监管对 BCA 的发展和应对有直接影响我们重点关注可能构成 NSP 基础的几种互补但迄今为止未被重视的机制。压力下的监视。 Topisirovic、Sonenberg、Mills 和 Ronai 博士之间富有成效的长期合作是现在扩展到包括梅勒博士，从而在以下领域提供广泛和互补的专业知识蛋白质合成和癌症生物学还包括纳米孔传感技术，能够解决我们将共同评估新发现的特定 NSP 调控因素。单独或协同发挥作用来调节细胞应激反应，特别是在 BCa 的情况下拟议的研究将：（1）建立生理学。 RACK1–JNK–eEF1A2 调节轴对细胞应激反应、生长和发育的重要性 (2) 评估应激诱导的多核糖体募集的作用。 Nedd8-Cullin 机制在调节 BCa 中 NSP 的衰变中的作用 (3) 确定的重要性。 UBQLN1 招募到多核糖体以在应激条件下调节新合成的蛋白质以及调节 BCa 对治疗的反应。我们提出的研究将确立新型 UPS 组件的重要性和意义。在细胞应激过程中控制蛋白质合成的调控网络，并利用 BCa 培养物和异种移植物、RPPA 技术和 TCGA 数据集挖掘的组合。