A Cereblon signaling network in Wnt-driven cancers

Wnt 驱动的癌症中的 Cereblon 信号网络

• 批准号: 10670555
• 负责人: Yasmath Ahmed
• 金额: $ 68.76万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670555
• 关键词: Animals; Apoptosis; Attenuated; Binding; Binding Proteins; Biochemical; Biological Markers; Bypass; Cancer Etiology; Cancer Model; Cause of Death; Cell Line; Cell Maintenance; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Colon; Colorectal Cancer; Complex; Cultured Cells; Data; Data Set; Development; Disease; Drosophila genus; Drug Targeting; Engineering; FDA approved; Genetic Engineering; Goals; Growth; Hematologic Neoplasms; Human; Human Engineering; Implant; In Vitro; Intestines; Knowledge; Malignant Neoplasms; Measures; Modeling; Molecular; Mus; Mutation; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Post-Translational Protein Processing; Proliferating; Proteins; Publishing; Regulation; Role; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Testing; Ubiquitination; United States; WNT Signaling Pathway; Work; Xenograft procedure; Zebrafish; anti-cancer; arm; beta catenin; cancer cell; casein kinase; cell behavior; cell growth; clinically relevant; colorectal cancer progression; drug development; druggable target; in vivo; inhibitor; innovation; loss of function; member; multidisciplinary; neoplastic cell; novel; novel therapeutic intervention; overexpression; receptor; reconstitution; recruit; small molecule; stem cells; translational potential; treatment strategy; tumor growth; tumor progression; tumorigenesis; ubiquitin-protein ligase

A Cereblon Signaling Network in Wnt-driven Cancers Abstract The long-term objective of this study is to investigate how Cereblon (CRBN) regulates the Wnt signal transduction pathway and to demonstrate how this can be exploited to target Wnt-driven colorectal cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance and aberrant activation of this pathway drives the initiation and progression of nearly all CRCs. To date, no drugs that inhibit the Wnt pathway have been FDA- approved, partly due to the lack of druggable targets that can bypass common Wnt pathway mutations in CRC. In a conceptual breakthrough, our recently published findings reveal that Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase that is a drug target in hematological malignancies, plays a critical role in Wnt signal transduction. We found that CRBN promotes the degradation of a subset of substrates, including Casein kinase 1α (CK1α), a negative regulator of Wnt signaling and a key component of the β-Catenin destruction complex. Moreover, Wnt stimulation induces the interaction of CRBN with CK1α to promote its ubiquitination and degradation. Furthermore, we showed that the role of CRBN in Wnt signaling is conserved in human cells, mouse intestinal organoids, zebrafish, and Drosophila. These studies demonstrate the first endogenous mechanism of CRBN regulation and provide a novel means of controlling Wnt pathway activity, with relevance for animal development and disease. The goal of this project is to use in vitro, ex vivo, and in vivo approaches to gain a better understanding of how the clinically relevant anti-cancer target, CRBN, promotes Wnt signal transduction. The three specific aims are to: 1) Identify the mechanisms by which Wnt stimulation activates CRBN; 2) Identify Wnt-stimulated CRBN interactors that regulate tumorigenesis; and 3) elucidate the role of CRBN in Wnt-dependent cancer progression. Because CRBN is a well-studied target for the development of drugs to treat hematological malignancies, the knowledge gained from this study will aid in the development of more selective small molecules as well as suggest innovative treatment strategies for CRC and other Wnt-driven cancers.

Wnt驱动的癌症中的Cereblon信号网络 摘要 本研究的长期目标是研究Cereblon（CRBN）如何调节Wnt信号转导 这是一个新的研究方向，旨在研究Wnt通路，并证明如何利用这一途径来靶向Wnt驱动的结直肠癌（CRC）。Wnt 信号传导对于肠干细胞的维持是必不可少的，并且该途径的异常激活驱动肠干细胞的增殖。 几乎所有CRC的启动和进展。到目前为止，FDA还没有发现抑制Wnt通路的药物。 批准，部分原因是缺乏可以绕过CRC中常见Wnt途径突变的药物靶点。 在一个概念上的突破，我们最近发表的研究结果表明，Cereblon（CRBN），基板 CRL 4CRBN E3泛素连接酶的受体是血液恶性肿瘤的药物靶点， 在Wnt信号转导中的作用。我们发现CRBN促进了一部分底物的降解， 包括酪蛋白激酶1α（CK 1 α），一种Wnt信号的负调节因子，也是β-连环蛋白的关键成分。 毁灭情结此外，Wnt刺激诱导CRBN与CK 1 α相互作用，以促进其在细胞内的表达。 泛素化和降解。此外，我们发现CRBN在Wnt信号传导中的作用在细胞中是保守的。 人类细胞、小鼠肠道类器官、斑马鱼和果蝇。这些研究表明， CRBN调节的内源性机制，并提供控制Wnt途径活性的新手段， 与动物发育和疾病的关系。本项目的目标是在体外、离体和体内使用 更好地了解临床相关抗癌靶点CRBN如何促进Wnt的方法 信号转导这三个具体目标是：1）确定Wnt刺激激活的机制 CRBN; 2）鉴定调节肿瘤发生的Wnt刺激的CRBN相互作用物;和3）阐明Wnt刺激的CRBN相互作用物的作用。 CRBN在Wnt依赖性癌症进展中的作用由于CRBN是一个经过充分研究的发展目标， 治疗血液恶性肿瘤的药物，从这项研究中获得的知识将有助于开发 更有选择性的小分子，并建议创新的治疗策略，为CRC和其他Wnt驱动的 癌的