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: 9096055
• 负责人: Richard N Kitsis
• 金额: $ 15.13万
• 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 2017-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096055
• 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; 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; 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（由申请人提供）：我们的研究申请正在解决PQ 8：“为什么某些突变事件在某些组织中促进癌症表型，而在其他组织中不促进？“我们提出的研究的目标是确定肿瘤抑制基因失活后组织选择性肿瘤发生的因素。多发性内分泌瘤1型（MEN 1）是一种以组织限制性肿瘤发生为特征的家族性癌症综合征，为实现这一目标提供了一个独特且易于处理的模型。Men 1是一种编码转录因子menin的普遍表达的肿瘤抑制因子，其双等位基因失活是MEN 1肿瘤发生所必需的。我们使用Men 1的Cre-lox缺失的实验表明，Men 1在各种组织中的差异失活并不能解释Men 1中肿瘤的组织限制性性质。相反，需要额外的因子来增强或抑制失去Men 1的组织中的肿瘤发生。例如，在胰腺的所有细胞中Men 1的纯合缺失导致内分泌组织而非外分泌组织中的肿瘤 同一个器官。鉴于Men 1的失活与MEN 1紧密相关，我们假设这些调节因子的运作受menin缺失的调控。我们的中心假设是menin的缺失差异调节影响各种组织中致癌作用的因子的表达，从而产生MEN 1中肿瘤形成的组织限制性特征。为了验证这一假设，我们建议采取无偏的，全基因组筛选和候选方法来确定相关因素。目的1分别采用ChIP-Seq和RNA-Seq来鉴定menin的DNA结合位点，所述DNA结合位点在发生MEN 1肿瘤的组织中与在不发生MEN 1肿瘤的组织中相比被差异占据，并且转录组在发生MEN 1肿瘤的组织中差异表达。具体来说，我们将比较内分泌胰腺（发生肿瘤）与外分泌胰腺（不发生肿瘤）的组织。目的2将验证这些发现在甲状旁腺，第二个网站的肿瘤发展MEN 1。目标3将探索候选蛋白ARC的作用，ARC是一种细胞凋亡抑制剂和细胞周期促进剂，已与乳腺癌发生有关。我们的初步研究表明，ARC是上调删除Men 1的胰腺内分泌和甲状旁腺，但不是在胰腺外分泌。此外，ChIP-CHIP研究表明menin与nol 3的启动子结合，nol 3是编码ARC的基因。总之，这些研究将提供新的和重要的见解，为什么肿瘤在某些组织中发展，而不是在其他组织中丢失肿瘤抑制基因。