Histone methylation and transcriptional by the menin tumor suppresor

项目概述：Menin由MEN1基因编码，最初被发现是因为它与多发性内分泌瘤（MEN1）有关，MEN1是一种常染色体显性癌症综合征。MEN1基因在大多数细胞类型的发育过程中表达，然而menin的突变或缺失通常会导致垂体、甲状旁腺、肺和肠胰腺组织内的肿瘤发生。最近，研究表明menin与混合白血病谱系（MLL）和MLL2蛋白复合物协同作用，调节细胞周期蛋白依赖性激酶抑制剂p18和p27的表达。这些基因的激活依赖于MLL/MLL2蛋白复合物的组蛋白甲基转移酶活性。研究目的是研究menin在MLL/MLL2复合物募集靶基因中的作用，并了解这些复合物如何调节基因表达。为了研究menin在内分泌组织中作为肿瘤抑制因子的功能，我们将使用Men1小鼠模型，该模型产生一系列与在人类中观察到的肿瘤相当的肿瘤。基因表达谱、染色质免疫沉淀和免疫纯化分析将用于建立胰岛内脑膜蛋白介导的基因激活模型。具体目标：1；小鼠胰岛中menin转录靶基因的鉴定。2. 确定menin-MLL/MLL2复合物在胰腺β细胞内调节染色质结构和促进基因激活中的作用。3. 研究menin的翻译后修饰及其对复合物形成和细胞功能的影响。癌症相关性：目前，人们对脑膜蛋白作为肿瘤抑制因子的作用机制知之甚少，也不清楚脑膜蛋白突变或缺失时内分泌组织易发生肿瘤的原因。这些研究将为进一步研究menin和MLL/MLL2蛋白复合物介导胰腺基因表达的分子机制奠定基础。这些研究的长期目标是确定细胞内可以被特异性抑制以控制细胞增殖的治疗靶点。

DESCRIPTION (provided by applicant): 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 beta cells. 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.