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，既包含酶变型活性，既可以将蛋白质交联蛋白与其他蛋白质或多胺交联，并且具有类似于其他经典GTP结合蛋白的GTP结合能力。尽管关于GTP结合TGASE的信号转导效应的信息有限，但已经对TGASE的跨启动过程进行了充分的研究。 TGASE的跨增强功能通过将供体谷氨酰胺残基与受体初级氨基组共价链接的反应通过将蛋白交联到其他蛋白质或多胺通过将其交联到其他蛋白质或多胺来对蛋白质进行跨增化功能。 TGase与这些新蛋白质蛋白或蛋白质聚酰胺复合物的产生有关调节正常细胞过程，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，白内障和神经退行性疾病的进展有关。我们和其他人表明，视黄酸（RA）诱导的细胞分化紧密耦合，以增加TGASE的GTP结合和跨增强活性。这与观察到TGase经常被环境应力上调的观察结果表明，TGase可以在分化或细胞应激条件下确保细胞存活。为了调查这种可能性，我们将确定：（1）TGase参与保护细胞免受凋亡的影响，并评估TGase的GTP结合和/或跨化活性是否对于发生这种生物学反应至关重要，（2）通过在细胞中调节TGASE活性在细胞中如何通过纯化的TGase调节因素和（3）不同的因素和（3）不同的（3）动态（3）动作来调节（3）。