New mechanisms for modulating the MALT1 oncoprotein

调节 MALT1 癌蛋白的新机制

• 批准号: 10092117
• 负责人: PETER C LUCAS
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-13 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092117
• 关键词: Affect; Antigen Receptors; Antigens; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; Binding; Biochemical; Biological; Biological Process; Biology; Cells; Cleaved cell; Clinical; Complex; Coupled; Cytoplasmic Protein; Development; Diagnosis; Evaluation; Event; G protein coupled receptor kinase; G-substrate; GTP-Binding Protein Regulators; Goals; Growth; Human; Immunologic Deficiency Syndromes; In Vitro; Intervention; Investigation; Knowledge; Laboratories; Lead; Lymphocyte; Lymphocyte Activation; Lymphoma; Lymphomagenesis; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mantle Cell Lymphoma; Mediating; Molecular; Movement; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Mutation; N-terminal; Oncoproteins; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Pharmacologic Substance; Phenotype; Phosphotransferases; Plant Roots; Play; Protein Region; Proteins; Recurrence; Regulation; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Specimen; Structure; Study models; Therapeutic; Tumor Suppressor Proteins; United States; Xenograft Model; adaptive immune response; antitumor effect; cell type; clinical application; curative treatments; design; driver mutation; gain of function; gain of function mutation; genetic analysis; immune health; improved; in vivo; inhibitor/antagonist; innovation; insight; large cell Diffuse non-Hodgkin' s lymphoma; mimetics; mucosa-associated lymphoid tissue; mucosa-associated lymphoid tissue lymphoma; mutant; novel; novel strategies; novel therapeutic intervention; prognostic; protein protein interaction; receptor; recruit; scaffold; small molecule; therapeutic protein; transcription factor; treatment strategy; tumor

PROJECT SUMMARY: Lymphoma is the sixth most common form of cancer in the United States, affecting an estimated 23 per 100,000 people. While there have been significant advances in our understanding of lymphoma biology and our ability to provide curative therapy, many patients with lymphoma continue to suffer poor outcomes with approximately 20,000 people dying from lymphoma in the US each year. Novel approaches to the diagnosis and treatment of lymphoma are urgently needed. This application is focused on elucidating the molecular mechanisms that regulate MALT1, a central oncoprotein in B-cell lymphoma. MALT1 is a cytoplasmic protein that serves to mediate antigen receptor- dependent lymphocyte activation, proliferation and survival, via stimulation of the canonical pro-survival NF-κB transcription factor. In B-lymphocytes, the antigen receptor is known as the B-cell receptor (BCR). In these cells, BCR-induced, MALT1-dependent NF-κB activation is a required event during the normal adaptive immune response, but dysregulated activation of this pathway can lead to lymphoma. Indeed, genetic analysis has revealed that in specific subtypes of B-cell lymphoma, malignant B cells highjack BCR signaling pathways in order to promote their own growth and survival. BCR stimulation results in assembly of the CARMA1-Bcl10-MALT1 (CBM) protein signaling complex, where MALT1 serves as the effector by carrying out two important functions. First, MALT1 acts as a scaffold to recruit and activate downstream signaling proteins, and second, MALT1 acts as a protease to cleave specific substrate signaling proteins and alter their activities. The critical importance of achieving appropriate regulation of MALT1 activity is demonstrated by the fact that gain-of-function mutations in BCR subunits or in CARMA1, resulting in exaggerated MALT1 activity, are recurrently detected in human B-cell lymphoma. Thus, MALT1 is the subject of intense investigation as a key regulator of B-lymphomagenesis and a promising new target for pharmaceutical inhibition. This proposal investigates the innovative hypothesis that specific proteins are capable of controlling MALT1 function, such that their loss in some subtypes of B-cell lymphoma may contribute to aberrant MALT1 activity. The presence of gain-of-function BCR or CARMA1 mutants may synergize with loss of such proteins in promoting lymphomagenesis; conversely, loss alone may be pathogenic. Our goals for this proposal are to elucidate the molecular underpinnings by which specific protein-protein interactions can abrogate MALT1 activity, to determine how this interaction influences lymphocyte growth and survival, and to utilize this information to inform the design of novel therapeutic approaches to MALT1-dependent lymphoma.

项目摘要： 淋巴瘤是美国第六种最常见的癌症形式，估计影响23 100,000人。尽管我们对淋巴瘤生物学和 我们提供治疗疗法的能力，许多淋巴瘤患者的结局仍然不佳 每年美国大约有20,000人死于淋巴瘤。诊断的新颖方法 迫切需要淋巴瘤的治疗。 该应用的重点是阐明调节MALT1的分子机制（一种中央） B细胞淋巴瘤中的癌蛋白。 MALT1是一种细胞质蛋白，用于介导抗原受体 - 通过刺激规范的生存NF-κB，依赖性淋巴细胞激活，增殖和存活率 转录因子。在B淋巴细胞中，抗​​原受体称为B细胞受体（BCR）。在这些 细胞，BCR诱导的MALT1依赖性NF-κB激活是正常自适应期间所需的事件 免疫反应，但该途径的激活失调可能导致淋巴瘤。确实，遗传分析 在B细胞淋巴瘤的特定亚型中，恶性B细胞高JACK BCR信号通路 为了促进自己的成长和生存。 BCR模拟导致CARMA1-BCL10-MALT1（CBM）蛋白信号传导复合物的组装， MALT1通过执行两个重要功能作为效应子。首先，Malt1充当脚手架 募集和激活下游信号蛋白，其次，MALT1充当清除的蛋白 特定的底物信号传导蛋白并改变其活性。实现适当的至关重要的重要性 MALT1活性的调节是通过以下事实证明的 CARMA1在人类B细胞淋巴瘤中经常检测到夸张的MALT1活性。那， MALT1是B淋巴作用的关键调节剂的强烈调查的主题，并且有希望的新 药物抑制的靶标。 该提案调查了特定蛋白质能够控制的创新假设 MALT1功能，使其在B细胞淋巴瘤的某些亚型中的损失可能导致异常MALT1 活动。功能障碍BCR或Carma1突变体的存在可能会随着这种蛋白质的损失而协同 促进淋巴作用；相反，仅损失可能是致病性的。我们的这一建议的目标是 阐明特定蛋白质蛋白相互作用可以消除MALT1的分子基础 活性，确定这种相互作用如何影响淋巴细胞的生长和生存，并利用这一点 信息以告知新型治疗方法的MALT1依赖性淋巴瘤的设计。