Molecular Basis of Action of the Putative Oncogene BCL6

描述：(申请人提供)原癌基因bcl6编码一种 转录抑制因子是淋巴细胞正常发育所必需的 和炎症的调节。防止染色体易位的 BCL-6在B细胞发育过程中的正常下调可能与此有关 在两种亚型非霍奇金淋巴瘤的发生中。BCL-6正常 抑制与B细胞活化有关的基因转录 分化、炎症和细胞周期控制，以及不适当的 其中一些基因的抑制可能会导致淋巴瘤。这个 这项研究的目的是为了了解其分子机制。 BCL-6抑制作用。BCL-6包含一个蛋白质相互作用基序，称为 POZ结构域，它是蛋白质的主要阻遏结构域。我们有 发现BCL-6的POZ结构域与辅阻遏子N-COR和 SMRT，以及一种我们称为BCOR的新型辅阻遏子。引人注目的是，BCOR 选择性地与bcl-6POZ结构域相互作用，提示它可能扮演一个 在bcl6抑制中的作用尤为重要。在下面提出的工作中，我们 将研究这些辅阻遏子在bcl6抑制中的作用，并进行 BCOR复合体的生化分析及BCOR的遗传分析 功能。我们有三个主要目标。首先，我们将确定BCL.6是否 将特定的辅抑制子招募到特定的靶基因启动子，如果 那么，在什么情况下。第二，我们将进行生化提纯和鉴定 BCOR复合体的组件，并从功能上分析了少数 这些组件。第三，我们将使BCOR的小鼠有条件突变，并且 研究该基因的全局或特定细胞类型缺失的影响。这 这项工作旨在阐明bcl6如何正常调节靶基因以及如何 不适当的bcl6活性导致B细胞淋巴瘤。

DESCRIPTION: (provided by applicant) The proto-oncogene BCL-6 encodes a transcriptional repressor that is essential for normal lymphocyte development and regulation of inflammation. Chromosomal translocations that prevent the normal down regulation of BCL-6 during B cell development have been implicated in the generation of two subtypes of non-Hodgkins lymphoma. BCL-6 normally represses the transcription of genes involved in B cell activation, B cell differentiation, inflammation, and cell cycle control, and the inappropriate repression of some of these genes is likely to contribute to lymphoma. The objective of the proposed research is to understand the molecular mechanisms of BCL-6 repression. BCL-6 contains a protein-protein interaction motif called the POZ domain, which serves as the major repression domain of the protein. We have found that the POZ domain of BCL-6 interacts with the corepressors N-CoR and SMRT, as well as with a novel corepressor we called BCoR. Strikingly, BCoR interacts selectively with the BCL-6 POZ domain, suggesting that it may play a particularly important role in BCL-6 repression. In the work proposed below we will study the role of these corepressors in BCL-6 repression and perform a biochemical analysis of the BCoR complex and a genetic analysis of BCoR function. We have three main aims. First, we will determine whether BCL.6 recruits particular corepressors to particular target gene promoters, and if so, under what conditions. Second, we will biochemically purify and identify components of the BCoR complex, and functionally analyze a small number of these components. Third, we will make a conditional mouse mutant of BCoR, and study the effects of global or cell type-specific deletion of the gene. This work seeks to elucidate how BCL-6 regulates target genes normally and how inappropriate BCL-6 activity contributes to B cell lymphoma.