Histone methylation and transcriptional by the menin tumor suppresor

项目摘要： Menin由MEN 1基因编码，最初被鉴定是因为它参与了多个 Endocine Neoplasia（MEN 1），一种常染色体显性遗传癌症综合征。MEN 1基因表达于 大多数细胞类型在整个发育过程中，然而突变或删除menin通常会导致 垂体、甲状旁腺、肺和肠胰腺组织内的肿瘤发生。近日有 显示menin与混合性白血病谱系（MLL）和MLL 2蛋白协同作用 复合物来调节细胞周期蛋白依赖性激酶抑制剂p18和p27的表达。激活 这些基因的表达依赖于MLL/MLL 2蛋白的组蛋白甲基转移酶活性 配合物本研究的目的是探讨menin在MLL/MLL 2招募中的作用 复合物靶向基因，并了解这些复合物如何调节基因表达。探讨 menin如何在内分泌组织中作为肿瘤抑制因子发挥作用，我们将使用Men 1 +/-小鼠模型 它会产生一系列肿瘤，这些肿瘤与在人类中观察到的肿瘤相当。基因表达 将进行谱分析、染色质免疫沉淀和免疫纯化测定，以建立 胰岛内menin介导的基因激活的模型。 具体目标： 1.小鼠胰岛中menin转录靶基因的鉴定。 2.确定menin-MLL/MLL 2复合物在调节染色质结构和促进细胞凋亡中的作用。 胰腺β细胞内基因活化。 3.研究menin的翻译后修饰及其对复合物形成的影响， 细胞功能 癌症相关性：目前，对menin如何作为肿瘤抑制因子或 为什么当menin突变或缺失时，内分泌组织容易发生肿瘤。这些研究将 为研究menin和MLL/MLL 2蛋白介导的分子机制提供基础 胰腺基因表达的复合物。这些研究的长期目标是确定治疗 可以特异性抑制细胞内的靶点以控制细胞增殖。

Project Summary: Menin is encoded by the MEN1 gene and was initially identified because of its involvement in Multiple Endocine Neoplasia (MEN1), an autosomal dominant cancer syndrome. The MEN1 gene is expressed in most cell types throughout development, however mutation or deletion of menin typically results in tumorigenesis within the pituitary, parathyroid, lungs and enteropancreatic tissues. Recently, it has been shown that menin functions in collaboration with Mixed Leukemia Lineage (MLL) and MLL2 protein complexes to regulate the expression of the cyclin-dependent kinase inhibitors p18 and p27. The activation of these genes was dependent upon the histone methyltransferase activity of the MLL/MLL2 protein complexes. The research objective is to examine the role of menin in the recruitment of MLL/MLL2 complexes to target genes and understand how these complexes regulate gene expression. To investigate how menin functions as a tumor suppressor within endocrine tissue, we will use a Men1+/- mouse model that develops an array of tumors that is comparable to what is observed in humans. Gene expression profiling, chromatin immunoprecipitation and immunopurification assays will be performed to establish a model for menin mediated gene activation within the panceatic islet. Specific Aims: 1. Identify transcriptional target genes of menin in mouse pancreatic islets. 2. Determine the role of the menin-MLL/MLL2 complexes in modulating chromatin structure and facilitating gene activation within the pancreatic (3cells. 3. Investigate the post-translational modifications of menin and their effects on complex formation and cellular function. Cancer Relevance: At this time, very little is known about how menin functions as a tumor suppressor or why endocrine tissue is susceptible to neoplasia when menin is mutated or absent. These studies will provide a foundation for studying the molecular mechanisms mediated by menin and MLL/MLL2 protein complexes in pancreatic gene expression. The long-term goal of these studies are to identify therapeutic targets within the cell that could be specifically inhibited to control cellular proliferation.