Role of CSN in the activity and dynamic cycling of cullin-RING ubiquitin ligases

CSN 在 cullin-RING 泛素连接酶活性和动态循环中的作用

基本信息

批准号：
9188804
负责人：
SETH M COHEN
金额：
$ 32.77万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188804
关键词：
Active Sites Affinity Chromatography Antineoplastic Agents Architecture Behavior Biochemical Biological Biological Assay Biology COPS5 gene Cancer Etiology Cancer Model Cell Proliferation Cell physiology Cells Chemicals Chemotherapy-Oncologic Procedure Clinical Trials Complex Cullin Proteins Data Development Digit structure Discrimination Dominant-Negative Mutation Drug Targeting Enzymes Event Excision Exhibits Family Fission Yeast Foundations Future Genetic Genetic study Guanine Nucleotide Exchange Factors HDAC1 gene Human IL27RA gene Isotope Labeling KRAS2 gene Knowledge Link Malignant Neoplasms Mass Spectrum Analysis Mediating Metalloproteases Methods Modification Molecular Bank Molecular Genetics Monitor Multiple Myeloma Mutation Normal Cell Oncogenic Pathogenesis Pathway interactions Periodicity Pharmaceutical Preparations Physiological Processes Play Population Positioning Attribute Post-Translational Protein Processing Proteins Proteome Proteomics Protocols documentation Publishing Reagent Regulation Research Role Structure-Activity Relationship Testing Thalidomide Tumorigenicity Ubiquitin Like Proteins United States National Institutes of Health Work Zinc biophysical analysis cancer cell cancer therapy carbonate dehydratase experimental study genetic approach human disease inhibitor/antagonist isopeptidase lenalidomide novel overexpression preclinical study preference public health relevance receptor repository response scaffold small molecule libraries targeted treatment tool ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The cullin-RING ubiquitin ligase (CRL) family contains upwards of 240 ubiquitin ligases that regulate a broad range of cellular and organismal processes. Consistent with their critical roles in regulatory biology, CRLs have been intimately linked to human disease pathogenesis and therapy: mutations in CRL subunits underlie the development of several human cancers and CRL4CRBN has been implicated as the target of the anti- myeloma agent Thalomid. CRL pathways are regulated by multiple mechanisms, including dynamic cycles of CRL assembly/disassembly and post-translational modification of the cullin subunit by the ubiquitin-like protein Nedd8. CSN is a Nedd8 isopeptidase that regulates CRLs by removing the Nedd8 modification. Removal of Nedd8 from a CRL results in its deactivation and renders its substrate receptor susceptible to disassembly by the exchange factor, Cand1. Although the isopeptidase activity of CSN inhibits CRL activity, genetic studies indicate that CSN is a positive regulator of CRLs, which suggests that periodic deactivation and disassembly of CRLs is required to sustain CRL activity. Recently, the Nedd8 conjugation pathway has emerged as a drug target for cancer chemotherapy and the active site subunit of Csn5 has been implicated in sustaining tumorigenicity in a Myc-driven cancer model. Together, these data point to dynamic cycling of CRLs as being critical for cancer cell proliferation. The over-arching hypotheses that animate this project are that CSN plays a critical role in regulating the activity of CRL enzymes and architecture of the CRL network, and that perturbation of CSN activity is toxic to cancer cells. We plan to explore these topics in three Specific Aims. In Aim 1 we will use quantitative multidimensional mass spectrometry to characterize the architecture and dynamics of the CRL proteome. In Aim 2, we will characterize a novel non-enzymatic CRL-inhibitory activity of CSN. In Aim 3, we will generate a CSN isopeptidase inhibitor to use as a research tool and to evaluate whether CSN is a promising target for chemotherapy of cancer.

描述（由申请人提供）：cullin-RING 泛素连接酶 (CRL) 家族包含超过 240 种泛素连接酶，可调节广泛的细胞和生物过程。与它们在调节生物学中的关键作用相一致，CRL 与人类疾病的发病机制和治疗密切相关：CRL 亚基的突变是多种人类癌症发展的基础，而 CRL4CRBN 已被认为是抗骨髓瘤药物 Thalomid 的靶点。 CRL 通路受多种机制调节，包括 CRL 组装/分解的动态循环以及泛素样蛋白 Nedd8 对 cullin 亚基的翻译后修饰。 CSN 是一种 Nedd8 异肽酶，通过去除 Nedd8 修饰来调节 CRL。从 CRL 中去除 Nedd8 会导致其失活，并使其底物受体容易被交换因子 Cand1 分解。尽管 CSN 的肽酶活性抑制 CRL 活性，但遗传学研究表明 CSN 是 CRL 的正调节因子，这表明需要定期使 CRL 失活和分解来维持 CRL 活性。最近，Nedd8 缀合途径已成为癌症化疗的药物靶点，而 Csn5 的活性位点亚基与 Myc 驱动的癌症模型中维持致瘤性有关。总之，这些数据表明 CRL 的动态循环对于癌细胞增殖至关重要。推动该项目的首要假设是 CSN 在调节 CRL 酶的活性和 CRL 网络结构中发挥着关键作用，并且 CSN 活性的扰动对癌细胞有毒。我们计划在三个具体目标中探讨这些主题。目标 1 我们将使用定量多维质谱来表征 CRL 蛋白质组的结构和动力学。在目标 2 中，我们将表征 CSN 的新型非酶 CRL 抑制活性。在目标 3 中，我们将生成一种 CSN 异构肽酶抑制剂，用作研究工具并评估 CSN 是否是癌症化疗的有希望的靶点。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4.

酒精滥用药物双硫仑通过 p97 分离酶接头 NPL4 靶向癌症。

DOI：
发表时间：
2017
期刊：
影响因子：
64.8
作者：
Skrott, Zdenek;Mistrik, Martin;Andersen, Klaus Kaae;Friis, Søren;Majera, Dusana;Gursky, Jan;Ozdian, Tomas;Bartkova, Jirina;Turi, Zsofia;Moudry, Pavel;Kraus, Marianne;Michalova, Martina;Vaclavkova, Jana;Dzubak, Petr;Vrobel, Ivo;Pouckova, Pav
通讯作者：
Pouckova, Pav

Structural biology: Corralling a protein-degradation regulator.

结构生物学：捕获蛋白质降解调节剂。

DOI：
发表时间：
2014-08-14
期刊：
影响因子：
64.8
作者：
Deshaies; Raymond J
通讯作者：
Raymond J

Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11.

桥二硫二酮哌嗪通过靶向蛋白酶体去泛素酶 Rpn11 抑制蛋白质降解。

DOI：
10.1016/j.chembiol.2018.07.012
发表时间：
2018-11-15
期刊：
Cell chemical biology
影响因子：
8.6
作者：
Li J;Zhang Y;Da Silva Sil Dos Santos B;Wang F;Ma Y;Perez C;Yang Y;Peng J;Cohen SM;Chou TF;Hilton ST;Deshaies RJ
通讯作者：
Deshaies RJ

Targeting Metalloenzymes for Therapeutic Intervention.

靶向金属酶进行治疗干预。

DOI：
10.1021/acs.chemrev.8b00201
发表时间：
2019-01-23
期刊：
Chemical reviews
影响因子：
62.1
作者：
Chen AY;Adamek RN;Dick BL;Credille CV;Morrison CN;Cohen SM
通讯作者：
Cohen SM

Correction to Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

对蛋白酶体亚基 Rpn11 抑制剂的发现进行修正。

DOI：
发表时间：
2017-04-13
期刊：
影响因子：
7.3
作者：
Perez, Christian;Li, Jing;Parlati, Francesco;Rouffet, Matthieu;Ma, Yuyong;Zhou, Han;Mackinnon, Andrew L;Chou, Tsui;Deshaies, Raymond J;Cohen, Seth M
通讯作者：
Cohen, Seth M