Molecular Basis of Action of the Putative Oncogene BCL6

描述：（由申请人提供）原癌基因BCL-6编码一种 正常淋巴细胞发育所必需的转录抑制因子 和调节炎症。染色体易位阻止了 在B细胞发育过程中BCL-6的正常下调已经被暗示 两种非霍奇金淋巴瘤亚型的产生。BCL-6正常 抑制参与B细胞活化、B细胞 分化，炎症和细胞周期控制，以及不适当的 这些基因中的一些基因的抑制可能有助于淋巴瘤。的 这项研究的目的是了解 BCL-6抑制。BCL-6含有一个蛋白质-蛋白质相互作用基序，称为 POZ结构域，其作为蛋白质的主要阻遏结构域。我们有 发现BCL-6的POZ结构域与辅阻遏物N-CoR相互作用， SMRT，以及一种新的辅阻遏物，我们称之为BCoR。令人惊讶的是，BCoR 选择性地与BCL-6 POZ结构域相互作用，这表明它可能发挥作用。 在BCL-6抑制中起重要作用。在下文提出的工作中， 将研究这些辅助抑制因子在BCL-6抑制中的作用，并进行一项研究。 BCoR复合物的生化分析和BCoR的遗传分析 功能我们有三个主要目标。首先，我们将确定是否BCL.6 募集特定的辅阻遏物到特定的靶基因启动子，如果 那么在什么条件下呢。第二，我们将生化纯化和鉴定 BCoR复合物的组成部分，并在功能上分析了少数 这些组件。第三，我们将制造BCoR的条件突变小鼠， 研究基因的整体或细胞类型特异性缺失的影响。这 这项工作旨在阐明BCL-6如何正常调节靶基因，以及如何 不适当的BCL-6活性有助于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.