Deciphering the Tissue Specificity of MEN1 Related Tumorigenesis

破译 MEN1 相关肿瘤发生的组织特异性

• 批准号: 9122791
• 负责人: Richard N Kitsis
• 金额: $ 30.99万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122791
• 关键词: Accounting; Address; Age-Months; Alleles; Apoptosis; Apoptosis Inhibitor; Applications Grants; Binding; Binding Sites; Biological; Cell Cycle; Cells; ChIP-on-chip; ChIP-seq; Characteristics; DNA Binding; Development; Endocrine; Event; Exocrine pancreas; Experimental Designs; Gene Expression Profile; Genes; Germ Lines; Goals; Hereditary Malignant Neoplasm; Histocompatibility Testing; Informatics; Islets of Langerhans; Link; Malignant Neoplasms; Mammary Tumorigenesis; Menin; MicroRNAs; Modeling; Multiple Endocrine Neoplasia Type 1; Mus; Mutate; Nature; Organ; Pancreas; Parathyroid gland; Pathway interactions; Pattern; Phenotype; Play; Proteins; Regulation; Research; Role; Site; Specificity; Syndrome; Testing; Thyroid Gland; Tissues; Transcript; Tumor Suppressor Genes; Tumor Suppressor Proteins; Wild Type Mouse; carcinogenesis; cell type; differential expression; genome-wide; genome-wide analysis; insight; mortality; novel; operation; prevent; promoter; research study; survivorship; transcription factor; transcriptome sequencing; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Our research application is addressing PQ8: "Why do certain mutational events promote cancer phenotypes in some tissues and not in others?" The goal of our proposed research is to identify factors responsible for tissue-selective tumorigenesis following inactivation of a tumor suppressor gene. Multiple Endocrine Neoplasia type 1 (MEN1), a familial cancer syndrome characterized by tissue-restricted tumorigenesis, provides a unique and tractable model with which to accomplish this goal. Bi-allelic inactivation of Men1, a ubiquitously expressed tumor suppressor encoding the transcription factor menin, is required for tumorigenesis in MEN1. Our experiments using Cre-lox deletion of Men1 demonstrates that differential inactivation of Men1 in various tissues does not explain the tissue restricted nature of tumors in MEN1. Rather, additional factors are required to enhance or suppress tumorigenesis in tissues that have lost Men1. For example, homozygous deletion of Men1 in all cells of the pancreas results in tumors in the endocrine tissue but not exocrine tissue of the same organ. Given that inactivation of Men1 is tightly linked to MEN1, we postulate that operation of these modulating factors is regulated by loss of menin. Our central hypothesis is that loss of menin differentially regulates expression of factors that influence carcinogenesis in various tissues so as to generate the tissue restricted characteristic of tumor formation in MEN1. To test this hypothesis, we propose to undertake both unbiased, genome wide screens and candidate approaches to identify relevant factors. Aim 1 employs ChIP- Seq and RNA-Seq respectively to identify DNA binding sites for menin that are differentially occupied and transcriptomes that are differentially expressed in tissues that develop MEN1 tumors versus those that do not. Specifically, we will compare tissues from the endocrine pancreas (develops tumors) versus the exocrine pancreas (does not develop tumors). Aim 2 will validate these findings in the parathyroid gland, a second site of tumor development in MEN1. Aim 3 will explore the role of the candidate protein ARC, an apoptosis inhibitor and cell cycle promoter that has already been implicated in mammary carcinogenesis. Our preliminary studies show that ARC is up-regulated by deletion of Men1 in the endocrine pancreas and parathyroid gland, but not in the exocrine pancreas. Moreover, ChIP-CHIP studies suggest that menin binds to the promoter of nol3, the gene encoding ARC. Taken together, these studies will provide novel and important insights into why tumors develop in some tissues and not in others following loss of a tumor suppressor gene.

描述(申请人提供)：我们的研究申请涉及PQ8：“为什么某些突变事件会在一些组织中促进癌症表型，而在其他组织中不会？”我们提出的研究的目标是确定在肿瘤抑制基因失活后导致组织选择性肿瘤发生的因素。多发性内分泌肿瘤1型(MEN1)是一种以组织限制性肿瘤形成为特征的家族性癌症综合征，它为实现这一目标提供了一种独特且易于处理的模型。MEN1是一种普遍表达的肿瘤抑制因子，编码转录因子Menin，它的双等位基因失活是MEN1肿瘤发生所必需的。我们使用MEN1的Cre-lox缺失的实验表明，MEN1在不同组织中的差异失活并不能解释MEN1中肿瘤的组织限制性性质。相反，需要更多的因子来增强或抑制失去MEN1的组织中的肿瘤发生。例如，在胰腺的所有细胞中，MEN1的纯合缺失会导致内分泌组织中的肿瘤，但不会导致外分泌组织中的肿瘤 来自同一个器官。鉴于MEN1的失活与MEN1密切相关，我们假设这些调节因子的运作受到脑膜素丢失的调控。我们的中心假设是，脑膜素的丢失在不同的组织中差异地调节影响致癌的因子的表达，从而产生MEN1中肿瘤形成的组织限制性特征。为了验证这一假设，我们建议采用无偏见的全基因组筛查和候选方法来确定相关因素。目的1利用芯片序列和RNA序列分别鉴定MEN1肿瘤组织和非MEN1肿瘤组织中有差异表达的转录本和有差异表达的脑膜素DNA结合部位。具体地说，我们将比较内分泌胰腺组织(发生肿瘤)和外分泌胰腺组织(不发生肿瘤)。AIM 2将在甲状旁腺中验证这些发现，甲状旁腺是MEN1中肿瘤发展的第二个部位。目的3将探讨候选蛋白ARC的作用，ARC是一种细胞凋亡抑制因子和细胞周期促进剂，已被认为与乳腺癌的发生有关。我们的初步研究表明，在内分泌胰腺和甲状旁腺中，MEN1的缺失上调了ARC的表达，但在外分泌胰腺中没有上调。此外，芯片研究表明，薄荷素与编码ARC的基因nol3的启动子结合在一起。综上所述，这些研究将为肿瘤在某些组织中发展而不是在肿瘤抑制基因丢失后在其他组织中发展提供新的和重要的见解。