Control of Protein Synthesis by the UPS Under Stress

应激状态下 UPS 对蛋白质合成的控制

• 批准号: 9512865
• 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
• 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/9512865
• 关键词: Area; Attenuated; Breast Cancer Cell; Breast Cancer cell line; Cancer Biology; Cancer Cell Growth; 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; Regulation; Research; Resolution; Ribosomes; Role; Stress; System; Technology; The Cancer Genome Atlas; Time; Translating; Ubiquitin; Ubiquitination; Xenograft procedure; arm; base; 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; recruit; response; sensor technology; treatment response; ultraviolet irradiation

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.

项目摘要 该建议基于细胞应力反应的新发现的调节部门，从而 招募端子激酶（JNK）以翻译核糖体（多聚肌体）以介导新的降解 合成蛋白（NSP）。我们确定了这个新型调节模块对乳腺癌的重要性 （BCA）生物学，并识别第一次链接的泛素蛋白酶体系统（UPS）组件 随着NSP的监视。它们包括Cullin 2，Nedd8和Ubiquilin1（UBQLN1），我们证明 影响BCA细胞中的蛋白质合成。这些UPS成分在BCA基础中的表达失调 研究其在BCA发展和对治疗反应中的作用的理由。 我们的初步结果支持以下假设：NSP稳定性的控制构成了一个新的层 调节蛋白质合成/可用性，这反过来控制了细胞对胁迫的反应。我们 进一步假设，这种法规对BCA的发展和反应有直接影响 治疗。我们专注于几种完善但隐藏的未欣赏机制，这些机制可能是NSP的基础 压力下的监视。 DRS之间的生产和长期合作。 Topisirovic，Sonenberg，Mills和Ronai是 现在扩展到包括梅勒博士，从而在 蛋白质合成和癌症生物学也包括纳米孔感应技术，使能够解决 泛素链拓扑。我们将共同评估特定的，新确定的NSP调节因素 单独或共同调节细胞应力反应的功能，特别是在BCA的背景下 对治疗的发展和反应。拟议的研究将：（1）建立生理 RACK1 -JNK – EEF1A2调节轴对细胞应力反应，生长和 乳腺癌的治疗反应。 （2）评估应力诱导的多个多个募集的作用 NEDD8 – Cullin机械在确定BCA中NSP的衰减时。 （3）确定的重要性 UBQLN1在压力条件下确定新合成的蛋白质以确定新合成的蛋白质组 并调节BCA对治疗的反应。 我们提出的研究将确定精选UPS组成部分的重要性和意义 控制细胞应激过程中蛋白质合成的调节网络，并使用A在BCA中建立其作用 BCA培养物和异种移植物，RPPA技术和TCGA数据集采矿的结合。