BATF in Blood Cell Growth, Development and Malignancies

描述（由申请人提供）：激活蛋白1 （Activator Protein-1, AP-1）由二聚化碱性亮氨酸拉链转录因子组成，在细胞增殖、细胞存活和细胞死亡中起重要作用。最广为人知的AP-1家族成员Fos和Jun蛋白是所有主要细胞内信号通路的核靶点。因此，控制Fos:Jun异源二聚体活性的体内方法将在癌症和神经退行性疾病等多种疾病状态中找到临床应用。BATF和高度相关的蛋白JDP1在AP-1家族成员中是独一无二的，它们与Jun形成高亲和力二聚体，表现出与Fos:Jun二聚体相同的DNA结合偏好，但却没有激活基因转录的能力。因此，这些蛋白具有天然存在的AP-1负调节因子的特性，可以用来控制体内AP-1的活性。野生型和变体BATF蛋白组织特异性表达的转基因小鼠模型将被用于研究BATF介导的体内AP-1活性调节的生物学后果。由含有AP-1复合物的BATF调控的靶基因将使用一种结合染色质免疫沉淀和AP-1启动子微阵列筛选的新方法进行鉴定。BATF和JDP1功能失活的小鼠将揭示这些蛋白对哺乳动物生长发育的重要性，并将用于分析与选定组织中BATF介导的AP-1调节缺失相关的基因表达变化。最后，作为确定体内BATF表达调控策略的信号通路的第一步，控制BATF基因表达的调控元件和相关转录因子将被表征。在培养细胞中诱导BATF表达将用于验证在小鼠中鉴定的BATF靶基因，并探索由这些基因编码的蛋白质在与BATF表达相关的细胞表型中的作用（如果未知）。我们的短期目标是充分表征BATF对细胞中AP-1活性的影响，长期目标是利用这种独特的AP-1家族成员的特性（或基于BATF特性的分子策略）来控制经常与人类疾病相关的AP-1的异常活性。

DESCRIPTION (provided by applicant): Activator Protein-1 (AP-1) consists of dimerizing basic leucine zipper transcription factors and plays an essential role in cell proliferation, cell survival and cell death. The most well characterized AP-1 family members, the Fos and Jun proteins, are nuclear targets of all major intracellular signaling pathways. As a result, in vivo approaches to control the activities of the Fos:Jun heterodimer would find clinical applications in disease states as diverse as cancer and neurodegenerative disorders. BATF and the highly related protein, JDP1, are unique among AP-1 family members in that they form high affinity dimers with Jun that show the same DNA binding preference as Fos:Jun dimers, yet display no ability to activate gene transcription. Thus, these proteins possess the properties of naturally occurring, negative regulators of AP-1 that could be exploited to control AP-1 activity in vivo. Transgenic mouse models of tissue-specific expression of wild type and variant BATF proteins will be employed to examine the biological consequences of BATF-mediated modulation of AP-1 activity in vivo. Target genes that are regulated by BATF containing AP-1 complexes will be identified using a novel approach combining chromatin immunoprecipitation with AP-1 promoter microarray screening. Mice in which BATF and JDP1 have been functionally inactivated will reveal the importance of these proteins to mammalian growth and development and will be used to profile gene expression changes associated with the absence of BATF-mediated AP-1 regulation in selected tissues. Lastly, as a first step toward identifying signaling pathways that could be exploited for strategies to manipulate the levels of BATF expression in vivo, the regulatory elements and associated transcription factors that control BATF gene expression will be characterized. Inducible BATF expression in cultured cells will be used to validate BATF target genes identified in mice and to explore the role (if unknown) of the proteins encoded by these genes in the cellular phenotypes associated with BATF expression. Our short-term goal is to fully characterize the impact of BATF on AP-1 activity in cells, with the long-term goal of using the properties of this unique AP-1 family member (or molecular strategies based on the properties of BATF) to control the aberrant activity of AP-1 that is frequently associated with human disease.