Histone methylation and transcriptional by the menin tumor suppresor

项目总结： Menin由MEN1基因编码，最初被鉴定是因为它参与了多个 内分泌新生血管病(MEN1)，一种常染色体显性遗传癌症综合征。MEN1基因在 在发育过程中，大多数细胞类型，然而，脑膜素的突变或缺失通常会导致 肿瘤发生于脑下垂体、甲状旁腺、肺和肠胰腺组织。最近，它一直在 研究表明，膜蛋白与混合白血病谱系(MLL)和MLL2蛋白具有协同作用 调节细胞周期蛋白依赖性激酶抑制因子p18和p27表达的复合体。激活 这些基因中的一个依赖于MLL/MLL2蛋白的组蛋白甲基转移酶的活性 复合体。研究目的是研究薄荷素在MLL/MLL2招募中的作用 以靶基因为靶点的复合体，并了解这些复合体如何调节基因表达。去调查 如何在内分泌组织中发挥肿瘤抑制作用，我们将使用MEN1+/-小鼠模型 这会产生一系列肿瘤，可以与在人类身上观察到的肿瘤相媲美。基因表达 将进行概况分析、染色质免疫沉淀和免疫纯化分析，以建立 脑膜素介导的胰岛内基因激活模型。 具体目标： 1.鉴定小鼠胰岛脑膜素的转录靶基因。 2.确定Menin-MLL/MLL2复合体在调节染色质结构和促进 胰腺内的基因激活(3细胞。 3.研究脑膜素的翻译后修饰及其对复合体形成的影响 细胞功能。 癌症相关性：目前，人们对薄荷素作为肿瘤抑制因子的功能知之甚少 为什么内分泌组织在脑膜素突变或缺失时容易发生肿瘤？这些研究将 为研究脑膜素和MLL/MLL2蛋白介导的分子机制奠定了基础 复合体在胰腺中的基因表达。这些研究的长期目标是确定治疗方法 细胞内可被特异性抑制以控制细胞增殖的靶点。

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.