CHARACTERIZE TISSUE TRANSGLUTAMINASE FUNCTION/REGULATION

表征组织谷氨酰胺转氨酶功能/调节

• 批准号: 6298586
• 负责人: MARC A ANTONYAK
• 金额: $ 3.48万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6298586
• 关键词: apoptosis; biological signal transduction; cell proliferation; enzyme activity; protein glutamine gamma glutamyltransferase; retinoate; tissue /cell culture

Tissue transglutaminase (TGase) is a unique enzyme that contains both an enzymatic transamidation activity that crosslinks proteins to other proteins or polyamines and a GTP-binding capability similar to other classical GTP-binding proteins. Although there is limited information as to the signal transducing effects of GTP-bound TGase, the transamidation process of the TGase has been well studied. The transamidation function of TGase serves to posttranslationally modify proteins by cross-linking them to other proteins or polyamines through a reaction in which donor glutamine residues are covalently linked to acceptor primary amino groups. The generation of these new protein- protein or protein-polyamine complexes by TGase has been implicated in modulating normal cellular processes including: maintenance of the extracellular matrix network, cell differentiation, and apoptosis. On the other hand, aberrant TGase activity has also been linked to the progression of human cancers, cataracts, and neurodegenerative disorders. We and others have shown that retinoic acid (RA)- induced cell differentiation was tightly coupled to increases in both the GTP- binding and transamidation activities of the TGase. This, combined with the observations that the TGase is frequently up-regulated by environmental stresses, suggests that TGase may function to ensure cell survival under conditions of differentiation or cell stress. To investigate this possibility, we will determine: (1) the involvement of TGase in protecting cells from apoptosis and assess whether the GTP-binding and/or transamidation activity of the TGase is essential for this biological response to occur, (2) gain insight as to how TGase activity is regulated in cells by purifying a putative TGase regulatory factor, and (3) determine how differentiation factors other than RA mediate TGase activation.

组织转谷氨酰胺酶（TGase）是一种独特的酶，它既具有将蛋白质与其他蛋白质或多胺交联的酶转氨化活性，又具有与其他经典的gtp结合蛋白相似的gtp结合能力。虽然关于gtp结合的TGase的信号转导作用的信息有限，但TGase的转氨化过程已经得到了很好的研究。TGase的转氨功能是通过供体谷氨酰胺残基与受体一级氨基共价连接的反应，通过与其他蛋白质或多胺交联来修饰蛋白质的翻译后修饰。TGase产生的这些新的蛋白质-蛋白质或蛋白质-多胺复合物涉及调节正常的细胞过程，包括：维持细胞外基质网络，细胞分化和凋亡。另一方面，异常的TGase活性也与人类癌症、白内障和神经退行性疾病的进展有关。我们和其他人已经证明，维甲酸（RA）诱导的细胞分化与GTP结合和TGase转胺活性的增加紧密相关。结合TGase经常被环境胁迫上调的观察结果，表明TGase可能在分化或细胞应激条件下发挥作用，以确保细胞存活。为了研究这种可能性，我们将确定：(1)TGase参与保护细胞免于凋亡，并评估TGase的gtp结合和/或转酰胺活性是否对这种生物反应的发生至关重要，(2)通过纯化假定的TGase调节因子来了解TGase活性如何在细胞中调节，以及(3)确定除RA以外的分化因子如何介导TGase激活。