B-ATF IN B CELL GROWTH, DEVELOPMENT AND MALIGNANCIES

描述：组织特异性的功能表征 调节造血细胞生长和谱系的转录因子 发展将为设计战略提供分子靶点 操纵白血病表型。B-ATF是一种新型碱性亮氨酸拉链 (BZIP)以组织特异性方式表达并被诱导的蛋白质 EB病毒在人B细胞中的快速感染 EBV编码的反式激活蛋白EBNA-2的表达。B-ATF 是一种与Jun家族成员异源二聚的核蛋白 癌蛋白与AP-1靶DNA位点结合。在培养的细胞中 过表达B-ATF、Jun和Fos，AP-1反应性转录 记者基因被压抑。这表明B-ATF作为一种 AP-1的负调控因子，一种转录复合体，通常是 与诱导细胞生长有关。基于这些 观察到，目前尚不清楚为什么EBNA-2，一种病毒潜伏基因产物 B细胞永生化和转化所需的，触发 B-ATF的表达。进一步探讨EB病毒与人类免疫缺陷的关系 B-ATF，负责增强的顺式-反式调节机制 我们将研究EBNA-2对人B-ATF基因的表达。至 建立B-ATF在B细胞中的功能作用，实验将 以评估B-ATF对生化和生物学的影响 AP-1转录因子复合体的功能及其对酶活性的影响 一种额外表达的B-ATF相互作用蛋白(BIP-13) 尤其是在人类B细胞中。对时空的要求 B-ATF在体内的表达调控将通过原位研究 B-ATF基因表达谱的杂交法研究 胚胎和成年小鼠。转基因技术将用于建立 如果B-ATF表达的扰动对糖尿病的发展产生不利影响 整个动物。PI预计这些研究将阐明这一角色 研究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蛋白作为靶点在 B细胞恶性肿瘤的治疗。

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.