更新于：2024-05-01

SPOP

speckle type BTB/POZ protein

更新于：2024-05-01

基本信息

别名

BTBD32、HIB homolog 1、Roadkill homolog 1

+ [4]

简介

Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation. In complex with CUL3, involved in ubiquitination and proteasomal degradation of BRMS1, DAXX, PDX1/IPF1, GLI2 and GLI3. In complex with CUL3, involved in ubiquitination of MACROH2A1 and BMI1; this does not lead to their proteasomal degradation. Inhibits transcriptional activation of PDX1/IPF1 targets, such as insulin, by promoting PDX1/IPF1 degradation. The cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOP has higher ubiquitin ligase activity than the complex that contains the heterodimer formed by SPOP and SPOPL. Involved in the regulation of bromodomain and extra-terminal motif (BET) proteins BRD2, BRD3, BRD4 stability (PubMed:32109420).

关联

100 项与 SPOP 相关的临床结果

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100 项与 SPOP 相关的转化医学

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0 项与 SPOP 相关的专利（医药）

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493

项与 SPOP 相关的文献（医药）

2024-04-01·Food microbiology

Synergistic effect of the coculture of Leuconostoc pseudomesenteroides and Lactococcus lactis, isolated from honeybees, on the generation of plant-based dairy alternatives based on soy, pea, oat, and potato drinks

Article

作者: Sedo Molina, Guillermo Eduardo ; Shetty, Radhakrishna ; Jacobsen, Charlotte ; Duedahl-Olesen, Lene ; Hansen, Egon Bech ; Bang-Berthelsen, Claus Heiner

The production of plant-based dairy alternatives has been majorly focused on the improvement of sensorial, technological and nutritional properties, to be able to mimic and replace milk-based fermented products. The presence of off-flavours and antinutrients, the lack of production of dairy-like flavours or the metabolic inaccessibility of plant proteins are some of the challenges to overcome to generate plant-based dairy alternatives. However, in the present study, it is demonstrated how the synergistic effect of two LAB strains, when cocultured, can simultaneously solve those challenges when fermenting in four different plant-based raw materials: soy, pea, oat, and potato drinks (SPOP). The fermentation was performed through the mono- and co-culture of the two LAB strains isolated from Apis mellifera (honeybee): Leuconostoc pseudomesenteroides NFICC 2004 and Lactococcus lactis NFICC 2005. Firstly, the coculture of both strains demonstrated to increase the acidification rate of the four plant matrices. Moreover, L. pseudomesenteroides (LP) demonstrated to in situ produce high concentrations of mannitol when fructose was present as C-source. Furthermore, L. pseudomesenteroides, which encoded for PII-proteinase, demonstrated to break down SPOP proteins, releasing free amino acids that were used by L.lactis (LL) for growth and metabolism. Lastly, the analysis of their co-metabolic volatile performance showed the principal ability of removal of the main off-flavours found in SPOP, such as hexanal, 1-octen-3-ol, 2-pentylfuran, pentanal, octanal, heptanal, and nonanal, mainly led by L. pseudomesenteroides, as well as the production of dairy-like flavours, such as diacetyl and 3-methyl-1-butanol, triggered by L. lactis metabolism. Overall, these findings endorsed the use of honeybee isolated strains as starter cultures, demonstrated the potential of coupling genotypes and phenotypes of multiple strains to improve the organoleptic properties suggesting a potential of combining plant-based matrices for the generation of future high-quality plant-based dairy alternatives.

2024-02-10·Cellular and molecular life sciences : CMLS

BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma.

Article

作者: Zongdong Yu ; Xiang Wu ; Jie Zhu ; Huan Yan ; Yuxuan Li ; Hui Zhang ; Yeling Zhong ; Man Lin ; Ganghui Ye ; Xinming Li ; Jiabei Jin ; Kailang Li ; Jie Wang ; Hui Zhuang ; Ting Lin ; Jian He ; Changjiang Lu ; Zeping Xu ; Xie Zhang ; Hong Li ; Xiaofeng Jin

Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.

2024-02-08·ACS medicinal chemistry letters

Synthesis and Biological Evaluation of β-Lactam Derivatives Targeting Speckle-Type POZ Protein (SPOP).

Article

作者: Chenmao Zhou ; Xinyue Hao ; Zhengyang Chen ; Runze Zhang ; Qian Zhou ; Zisheng Fan ; Mingyue Zheng ; Hui Hou ; Sulin Zhang ; Hao Guo

Speckle-type POZ protein (SPOP) acts as a cullin3-RING ubiquitin ligase adaptor, which facilitates the recognition and ubiquitination of substrate proteins. Previous research suggests that targeting SPOP holds promise in the treatment of clear cell renal cell carcinoma (ccRCC). On the basis of the reported SPOP inhibitor 230D7, a series of β-lactam derivatives were synthesized in this study. The biological activity assessment of these compounds revealed E1 as the most potent inhibitor, which can disrupt the SPOP-substrate interactions in vitro and suppress the colony formation of ccRCC cells. Taken together, this study provided compound E1 as a potent inhibitor against ccRCC and offered insight into the development of the β-lactam SPOP inhibitor.

项与 SPOP 相关的新闻（医药）

2023-07-24

·生物谷

Nat Commun | 上海药物所郑明月团队提出基于序列的药物设计新方法

自上世纪90年代以来，基于蛋白质结构的药物设计（SBDD）一直是创新药物发现的主流方法，在针对具有明确靶标的疾病治疗方面取得了重大进步。这种方法一般涉及多个步骤的复杂流程，包括建立蛋白质的三维（3D）结构，识别潜在的配体结合位点，并通过虚拟筛选或全新设计发现活性化合物等等。SBDD流程中的每个步骤都有其局限性，例如许多蛋白质并没有高分辨率的结构。虽然近年来的蛋白质结构预测技术如AlphaFold和RoseTTAFold有所突破，但并非所有预测的结构都适合进行基于结构的药物设计。精确预测配体结合口袋是一个挑战，因为这些局部结构往往违反“蛋白质折叠规则”，配体的结合也会诱导氨基酸构象发生变化。此外，由于变构效应的机制多样性，对具有多个结构域的新靶标如何确定配体结合位点也存在困难。最后，虚拟筛选可能会产生假阳性，误差和错误的不断累积会导致最后的严重的假阳性问题。为了解决这些问题，中国科学院上海药物研究所郑明月团队提出了一种基于序列的药物设计新概念。这种“从序列到药物”（sequence-to-drug）的思路采用端到端的可微学习，直接从蛋白质序列出发进行药物设计发现，而无需经过上述多个中间步骤的复杂流程（图1）。图1. 基于序列的药物设计方法TransformerCPI2.0。a，基于结构药物设计与基于序列药物设计的流程对比。b，“从序列到药物”概念验证的三个阶段，包括：①评价跨蛋白质和化学空间的泛化能力（计算验证）；②通过耐药性突变和取代基活性悬崖效应的预测检验模型是否学习到蛋白质-配体相互作用知识（可解释性分析）；③开展具有挑战性的虚拟筛选和药物重定向预测（实验验证）。c，TransformerCPI2.0的架构。端到端的可微深度学习已经在计算机视觉和自然语言处理等领域产生了革命性的影响，它用可微基元（differentiable primitives）取代了复杂流程的所有组件，从输入端到输出端进行联合优化。AlphaFold2在蛋白质结构预测的成功也很大程度上依赖于端到端可微学习的思想。这个概念具有吸引力地方在于它可以以一种自洽和数据高效的方式执行整个学习建模过程，可能避免了复杂流程中的错误积累。相关研究论文以“Sequence-based drug design as a concept in computational drug design”为题于2023年7月15日在Nature Communications在线发表。尽管已经有深度学习研究报道可以基于蛋白质序列信息预测与化合物的相互作用，但是还没有一种模型完全验证了“从序列到药物”的药物设计概念。在这项工作中，研究团队设计了TransformerCPI2.0作为概念验证的基础模型。该模型利用Transformer神经网络架构和预训练蛋白质语言模型，在蛋白质和化学多样性空间中都展示出了泛化能力。对TransformerCPI2.0进行可解释分析，结果表明模型可以通过注意力机制从序列信息中有效学习蛋白质与配体分子间相互作用的抽象知识，而不仅是简单的记忆训练数据中的分布偏差。为了进一步检验基于蛋白质序列药物设计的可行性，研究团队还基于TransformerCPI2.0预测结果开展了湿实验的验证研究，针对多种具有挑战性的药物靶标成功发现活性化合物，包括：靶向E3泛素连接酶接头蛋白SPOP（配体结合位点为难以靶向的PPI作用界面）的新骨架抑制剂（图2）；靶向E3泛素连接酶RNF130（无蛋白晶体结构、无已知活性化合物）的结合分子。图2. 利用TransformerCPI2.0基于蛋白质序列发现新骨架SPOP抑制剂。此外，通过逆向应用TransformerCPI2.0对已上市药物进行蛋白质组范围的靶标筛选，成功发现雷贝拉唑抗肿瘤作用的潜在靶标ADP-核糖基化因子ARF1。这些新发现的活性分子和靶标蛋白都是模型训练过程未见的，表明TransformerCPI2.0可以推广到新的蛋白质和化学空间，显示了良好的泛化能力。计算分析和实验结果支持基于序列药物设计的可行性，基于这一概念的新方法有望成为未来理性药物设计流程的重要组成部分。这一工作通过计算机、信息学、化学和生物学等多学科融合交叉，为创新药物发现提供了新的视角。基于序列的方法可以作为基于结构药物设计的替代方法，在无法获得高质量蛋白质3D结构的场景中发挥作用，也可与其他虚拟筛选和高通量体外筛选技术结合，加速药物发现进程。最近，超大规模按需定制化合物库（make-on-demand library）技术快速发展，已覆盖了数亿到数十亿种化学物质的多样性空间，如何开发计算效率更高的虚拟筛选方法成为领域的研究热点。“从序列到药物”的端到端学习策略可以有效的简化建模和筛选流程，可以更加高效的探索未知化学和生物学空间，为原创药物的发现提供新的出发点和切入点。上海药物所研究生陈立凡，南京中医药大学联合培养研究生樊子生、常婕，博士后杨瑞瑞和侯辉为本文共同第一作者。上海药物所郑明月研究员、张素林副研究员为本文共同通讯作者。本研究得到了国家自然科学基金、临港实验室、国家重点研发专项、中科院青促会和上海市自然科学基金项目的基金资助。会议推荐会议详情会议名称：2023（第14届）细胞与基因治疗国际研讨会暨抗体工程与创新免疫治疗技术论坛暨2023细胞免疫治疗专业委员会年会主办单位：生物谷、梅斯医学、同济大学附属同济医院、南京可缘大会时间：9月22-23日大会地点：上海大会规模：1500人2010年至今，生物谷联合各合作单位已经顺利召开了13届细胞与基因治疗国际研讨会，与全球致力于细胞治疗行业同仁们一同成长沉淀，在提供行业信息交流平台的同时，也为基础研究提供了技术/产品等产业化的孵化平台。基于此，本届会议将继续以转化医学为切入点，以基础研究与临床应用相结合，针对细胞治疗的临床前沿研究、临床监管、治疗规范、细胞治疗安全性，免疫细胞新型疗法、实体瘤治疗、干细胞与癌症、抗体药物、核酸药物、基因编辑、肿瘤免疫治疗等热门议题进行讨论，诚邀国内外产学研医专家共聚，共绘产业发展新蓝图！长按识别二维码立即报名参会

2023-07-19

·生物谷

Nature子刊：上海药物所郑明月团队提出基于序列的药物设计新方法

通过逆向应用 Transformer CPI 2.0 对已上市药物进行蛋白质组范围的靶标筛选，成功发现雷贝拉唑抗肿瘤作用的潜在靶标ADP-核糖基化因子ARF1。这些新发现的活性分子和靶标蛋白都是模型训自上世纪90年代以来，基于蛋白质结构的药物设计（SBDD）一直是创新药物发现的主流方法，在针对具有明确靶标的疾病治疗方面取得了重大进步。这种方法一般涉及多个步骤的复杂流程，包括建立蛋白质的三维（3D）结构，识别潜在的配体结合位点，并通过虚拟筛选或全新设计发现活性化合物等等。SBDD流程中的每个步骤都有其局限性，例如许多蛋白质并没有高分辨率的结构。虽然近年来的蛋白质结构预测技术如AlphaFold和RoseTTAFold有所突破，但并非所有预测的结构都适合进行基于结构的药物设计。精确预测配体结合口袋是一个挑战，因为这些局部结构往往违反“蛋白质折叠规则”，配体的结合也会诱导氨基酸构象发生变化。此外，由于变构效应的机制多样性，对具有多个结构域的新靶标如何确定配体结合位点也存在困难。最后，虚拟筛选可能会产生假阳性，误差和错误的不断累积会导致最后的严重的假阳性问题。中国科学院上海药物研究所郑明月团队在 Nature 子刊 Nature Communications 期刊发表了题为：Sequence-based drug design as a concept in computational drug design 的研究论文。

2023-04-17

·PRNewswire

Caris Life Sciences to Showcase Research Highlighting the Clinical Value of Comprehensive Molecular Profiling at the American Association for Cancer Research Annual Meeting

Caris Life Sciences President, Dr. David Spetzler, to present on blood-based testing during a special session of the AACR Scientist↔Survivor Program® IRVING, Texas, April 14, 2023 /PRNewswire/ -- Caris Life Sciences®(Caris), the leading molecular science and technology company actively developing and delivering innovative solutions to revolutionize healthcare, today announced that the company and partners within the Caris Precision Oncology Alliance™ (POA) will collectively present four studies across 14 tumor types at the 2023 American Association for Cancer Research (AACR) Annual Meeting being held April 14-19, 2023 in Orlando, Florida, at Booth Number 130. Caris President, David Spetzler, M.S., Ph.D., MBA, will also lead an AACR Scientist↔Survivor Program® Special Session from 3:00 – 3:45 p.m. on Sunday, April 16 titled, "Early and Accurate: Leveraging Blood for Reliable Cancer Detection, Monitoring and Therapy Selection." Continue Reading "We are proud of the collaborative abstracts accepted for presentation at AACR, demonstrating the power of Caris' comprehensive molecular profiling and the large-scale collaboration between the growing number of POA sites," said Chadi Nabhan, M.D., MBA, FACP, Chairman of the Caris Precision Oncology Alliance. "The findings represent important observations, particularly in endometrial and prostate cancer, which enhance our understanding of the pathobiology of disease, potentially leading to novel therapeutics." Caris Life Sciences President, Dr. David Spetzler, to present on blood-based testing during a special session Tweet this "At Caris, our goal is to enable clinicians to make the best individualized treatment choices for their patients, researchers to discover new targets, and the biopharmaceutical industry to develop the next breakthrough medicines," said David Spetzler, M.S., Ph.D., MBA, President of Caris. "The diversity of the over 455,000 lifetime cases in Caris' unique AI-driven platform enables us to identify ethnic differences in the molecular and tumor microenvironment. Better understanding of these differences may help reduce ethnic health disparities and improve outcomes in cancer patients." Poster presentations include: Opposing roles of SPOP mutations in human prostate and endometrial cancers. (Poster Number: 937/20) April 16, 1:30 PM – 5:00 PM ET Molecular Characterization of Prostate Cancer Between Hispanic American and Non-Hispanic Whites: Implications for Cancer Ethnic Health Disparities. (Poster Number: 1895/1) April 17, 9:00 AM – 12:30 PM ET Pan-cancer analysis of XPO1 R749Q mutations across 217,570 patients. (Poster Number: 4253/2) April 18, 9:00 AM – 12:30 PM ET The Heterogeneous Immune and Molecular Landscape of Endometrial Cancer Metastases. (Poster Number: 4538/17) April 18, 9:00 AM – 12:30 PM ET Poster and abstract summaries highlighting this research will be available onsite at Caris' Booth Number 130. The full abstracts are available on the AACR website. Marking its 25th anniversary, the AACR Scientist↔Survivor Program® (SSP) is a unique program designed to build bridges and unity among the leaders of the scientific and cancer survivor and patient advocacy communities worldwide. By strengthening communications and forging partnerships between these important communities in the cancer field, the program enhances efforts to accelerate progress in the fight against cancer. Dr. David Spetzler will lead a special interest session at AACR's SSP, highlighting the importance and challenges facing blood-based cancer detection, monitoring and therapy selection and moderated by Anna Barker, Ph.D., FAACR, Chief Strategy Officer at the Lawrence J. Ellison Institute and founder and chair of the AACR Scientist↔Survivor Program®. The Caris Precision Oncology Alliance includes 82 cancer centers and academic institutions in the United States and beyond. These institutions have early access to the extensive database and artificial intelligence platform within Caris to establish evidence-based standards for cancer profiling and molecular testing in oncology. By leveraging the comprehensive genomic, transcriptomic and proteomic data available through Caris molecular profiling, Caris seeks to provide this network with the ability to prioritize therapeutic options and determine which clinical trial opportunities may benefit their patients. POA members are also able to integrate with a growing portfolio of biomarker directed trials sponsored by biopharma. Additionally, as a member of the POA, institutions have access to Caris CODEai™, the most comprehensive data solution in the industry with cancer treatment information and real-world clinical outcomes evidence for over 350,000 patients covering over 1 million data points per patient. About Caris Life Sciences Caris Life Sciences® (Caris) is the leading molecular science and technology company actively developing and delivering innovative solutions to revolutionize healthcare and improve patient outcomes. Through comprehensive molecular profiling (Whole Exome and Whole Transcriptome Sequencing) and the application of advanced artificial intelligence (AI) and machine learning algorithms, Caris has created the large-scale clinico-genomic database and cognitive computing needed to analyze and unravel the molecular complexity of disease. This information provides an unmatched resource and the ideal path forward to conduct the basic, fundamental research to accelerate discovery for detection, diagnosis, monitoring, therapy selection and drug development to improve the human condition. With a primary focus on cancer, Caris' suite of market-leading molecular profiling offerings assesses DNA, RNA and proteins to reveal a molecular blueprint that helps patients, physicians and researchers better detect, diagnose and treat patients. The company's latest advancement, Caris Assure™, is a blood-based, circulating nucleic acids sequencing (cNAS) assay that combines comprehensive molecular analysis (Whole Exome and Whole Transcriptome Sequencing from blood) and serial monitoring – making it the most powerful liquid biopsy assay ever developed. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Tokyo, Japan and Basel, Switzerland. Caris or its distributors provide services in the U.S., Europe, Asia and other international markets. To learn more, please visit CarisLifeSciences.com or follow us on LinkedIn. Caris Life Sciences Media Contact: Lisa Burgner [email protected] 214.294.5606 SOURCE Caris Life Sciences