CHARACTERIZE TISSUE TRANSGLUTAMINASE FUNCTION/REGULATION

表征组织谷氨酰胺转氨酶功能/调节

• 批准号: 6518901
• 负责人: MARC A ANTONYAK
• 金额: $ 4.42万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6518901
• 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.

组织转氨酶（TGase）是一种独特的酶，其含有将蛋白质交联至其他蛋白质或多胺的酶转酰胺活性和类似于其他经典GTP结合蛋白的GTP结合能力。尽管关于GTP结合的TGase的信号转导作用的信息有限，但是已经充分研究了TGase的转酰胺基过程。TGase的转酰胺功能用于通过将蛋白质与其他蛋白质或多胺交联来对蛋白质进行后修饰，所述交联是通过供体谷氨酰胺残基与受体伯氨基共价连接的反应进行的。通过TGase产生这些新的蛋白质-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：细胞外基质网络的维持、细胞分化和细胞凋亡。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。我们和其他人已经表明，视黄酸（RA）诱导的细胞分化与TG酶的GTP结合和转酰胺活性的增加密切相关。这与TGase经常被环境应激上调的观察结果相结合，表明TGase可能起作用以确保在分化或细胞应激条件下的细胞存活。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/或转酰胺活性是否是发生这种生物学应答所必需的，（2）通过纯化推定的TGase调节因子来了解细胞中TGase活性是如何调节的，和（3）确定RA以外的分化因子如何介导TGase活化。