BATF in Blood Cell Growth, Development and Malignancies

描述(申请人提供)：激活蛋白-1(AP-1)由碱性亮氨酸拉链转录因子二聚体组成，在细胞增殖、细胞存活和细胞死亡中发挥重要作用。AP-1家族中最具特点的成员是Fos和Jun蛋白，它们是所有主要的细胞内信号通路的核靶标。因此，体内控制Fos：Jun异源二聚体活性的方法将在癌症和神经退行性疾病等疾病状态中找到临床应用。在AP-1家族成员中，BATF和高度相关的蛋白JDP1是独一无二的，因为它们与Jun形成高亲和力的二聚体，表现出与Fos：Jun二聚体相同的DNA结合偏好，但不显示激活基因转录的能力。因此，这些蛋白质具有天然存在的AP-1负调控因子的特性，可用于在体内控制AP-1的活性。野生型和变异型BATF蛋白的组织特异性表达的转基因小鼠模型将被用来检验BATF介导的AP-1活性调节在体内的生物学后果。使用染色质免疫沉淀和AP-1启动子微阵列筛选相结合的新方法，将识别由含有AP-1复合体的BATF调控的靶基因。在BATF和JDP1功能失活的小鼠中，将揭示这些蛋白质对哺乳动物生长和发育的重要性，并将用于描述与BATF介导的AP-1在选定组织中缺失相关的基因表达变化。最后，作为确定可用于控制体内BATF表达水平的策略的信号通路的第一步，将对控制BATF基因表达的调节元件和相关转录因子进行表征。在培养细胞中可诱导的BATF表达将被用来验证在小鼠中发现的BATF靶基因，并探索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)。我们的短期目标是全面描述BATF对细胞内AP-1活性的影响，长期目标是利用这个独特的AP-1家族成员的特性(或基于BATF特性的分子策略)来控制AP-1的异常活性，而AP-1经常与人类疾病有关。

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.