B-ATF IN B CELL GROWTH, DEVELOPMENT AND MALIGNANCIES

B-ATF 在 B 细胞生长、发育和恶性肿瘤中的作用

• 批准号: 6350304
• 负责人: ELIZABETH J TAPAROWSKY
• 金额: $ 25.81万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-20 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350304
• 关键词: B lymphocyte; Epstein Barr virus; cell growth regulation; gene expression; gene induction /repression; gene targeting; genetic promoter element; genetically modified animals; hematopoietic stem cells; in situ hybridization; laboratory mouse; leukemia; leukocyte activation /transformation; neoplastic growth; nucleoproteins; oncoproteins; protein structure function; transcription factor; viral carcinogenesis

DESCRIPTION: The functional characterization of tissue-specific transcription factors that regulate hematopoietic cell growth and lineage development will provide molecular targets for the design of strategies to manipulate the leukemic phenotype. B-ATF is a new basic leucine zipper (bZIP) protein that is expressed in a tissue-specific manner and is induced rapidly in human B cells following infection with Epstein-Barr virus (EBV) and the expression of the EBV-encoded transactivator protein, EBNA-2. B-ATF is a nuclear protein that heterodimerizes with members of the Jun family of oncoproteins to bind to AP-1 target DNA sites. In cultured cells engineered to overexpress B-ATF, Jun, and Fos, transcription of an AP-1 responsive reporter gene is repressed. This suggests that B-ATF functions as a negative regulator of AP-1, a transcription complex that normally is associated with the induction of cellular growth. Based on these observations, it remains unclear why EBNA-2, a viral latency gene product required for B cell immortalization and transformation, triggers the expression of B-ATF. To explore further the relationship between EBV and B-ATF, the cis-trans regulatory mechanisms responsible for enhanced expression of the human B-ATF gene by EBNA-2 will be investigated. To establish a functional role for B-ATF in B cells, experiments will be performed to assess the impact of B-ATF on the biochemical and biological function of the AP-1 transcription factor complex and on the activities of an additional B-ATF-interacting protein (BIP-13) that is expressed preferentially in human B cells. The requirement for spatial and temporal control of B-ATF expression in vivo will be investigated using in situ hybridization to fully characterize the B-ATF gene expression pattern in embryonic and adult mice. Transgenic technology will be used to establish if perturbation of B-ATF expression adversely impacts the development of the whole animal. The PI anticipates that these studies will elucidate the role of B-ATF in B cell growth and development and provide the information needed to assess the feasibility of using this new bZIP protein as a target in the management of B cell malignancies.

描述：组织特异性 调节造血细胞生长和谱系的转录因子 开发将为设计策略提供分子靶点， 操纵白血病表型。 ATF是一种新型碱性亮氨酸拉链 （bZIP）蛋白，其以组织特异性方式表达并被诱导 感染EB病毒（EBV）后在人B细胞中迅速 以及EBV编码的反式激活蛋白EBNA-2的表达。 B-ATF 是一种核蛋白，与Jun家族成员异二聚化， 癌蛋白结合AP-1靶DNA位点。 在培养的细胞中， 为了过表达B-ATF、Jun和Fos，转录AP-1应答基因， 报告基因被抑制。 这表明B-ATF的功能是 AP-1的负调节因子，一种转录复合物， 与诱导细胞生长有关。 基于这些 观察，目前还不清楚为什么EBNA-2，一种病毒潜伏基因产物， B细胞永生化和转化所需的蛋白质， B-ATF的表达。 进一步探讨EB病毒与 B-ATF，负责增强的顺式-反式调节机制 将研究EBNA-2对人B-ATF基因的表达。 到 为了确定B-ATF在B细胞中功能作用，实验将 评估B-ATF对生物化学和生物学的影响。 AP-1转录因子复合物的功能以及 一种额外的B-ATF相互作用蛋白（BIP-13）， 优选在人B细胞中。 对空间和时间的要求 B-ATF在体内表达的控制将使用原位杂交技术进行研究。 杂交，以充分表征B-ATF基因表达模式， 胚胎和成年小鼠。 转基因技术将用于建立 如果B-ATF表达的干扰对肿瘤的发展产生不利影响， 整个动物。 PI预期这些研究将阐明 B-ATF在B细胞生长发育中的作用，并提供所需信息 为了评估使用这种新的bZIP蛋白作为靶点的可行性， B细胞恶性肿瘤的管理。