Menin-mediated epigenetic tumor suppression

Menin 介导的表观遗传肿瘤抑制

基本信息

批准号：
8840193
负责人：
Xianxin Hua
金额：
$ 33.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-18 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840193
关键词：
Ablation Acute Affect Beta Cell Binding CCND1 gene CDK4 gene CDK6-associated protein p18 Cell Proliferation Clinical Trials Cultured Cells Cyclin D1 Cyclin-Dependent Kinase Inhibitor Development Disease Endocrine Gland Neoplasms Endocrine Glands Epigenetic Process Excision Gene Expression Genes Genetic Transcription Goals Health Hormones Human Inherited Investigational Therapies Islet Cell Tumor Knock-out Knockout Mice Lead Link Malignant Neoplasms Mediating Menin Methyltransferase Modeling Molecular Multiple Endocrine Neoplasia Type 1 Mus Mutate Mutation Neoplasms Neuroendocrine Tumors Neurosecretory Systems Nuclear Protein Organ Pathway interactions Patients Phenocopy Phosphorylation Protein-Arginine N-Methyltransferase Regulation Role Scaffolding Protein Structure Study models Syndrome Testing Translations Tumor Suppression Tumor Suppressor Proteins arginine methyltransferase effective therapy epigenetic regulation improved inhibitor/antagonist insight islet mortality mouse model neoplastic cell novel smoothened signaling pathway targeted treatment transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to elucidate the molecular mechanisms for inherited multiple endocrine neoplasia type 1 (MEN1) syndrome and pave the way to develop novel and improved therapy. MEN1 syndrome, characterized by the development of tumors in several endocrine organs, results from a mutation in the MEN1 gene, which encodes a tumor suppressor, menin. As the MEN1 gene is also mutated in ~40% of patients with sporadic neuroendocrine tumors, understanding how menin represses MEN1 tumors will likely provide new insights into how MEN1 tumors and other sporadic endocrine tumors develop. Targeted therapy against MEN1 syndrome is lacking yet highly desirable. Mouse models with ablation of the Men1 gene closely phenocopy MEN1 tumor syndrome, serving as reliable models for studying human menin's tumor suppressing function. Menin is a scaffold protein with multiple functions including regulation of gene transcription. One of menin's roles is to increase expression of anti-proliferative cyclin-dependent kinase inhibitors (CDKIs), p18 and p27. However, little is known as to whether or how menin represses expression of pro-proliferative genes. Our recent studies solved the co-crystal structure in which menin binds JunD, a transcription factor, with a deep pocket, and showed that menin inhibits JunD's function by suppressing its phosphorylation and transcriptional activity. Moreover, acute Men1 excision, in the islets of mice, induced expression of multiple pro-proliferative genes, as well as components of the pro-proliferative Hedgehog (Hh) signaling pathway. Further, we uncovered that menin directly interacts with a transcription-repressing histone arginine methyltransferase in suppressing Hh signaling-related genes. We hypothesize that menin functionally interacts with JunD and the methyltransferase to repress expression of pro-proliferative genes, as well as the genes that promote Hedgehog signaling, and that pharmacological suppression of Hh signaling is effective for treating MEN1 tumors. To test these hypotheses Aim 1 will investigate how menin epigenetically controls expression of cyclin D1 via regulating JunD and the arginine methyltransferase, and its interplay with the menin-regulated CDKI axis in neuroendocrine tumor cells. Aim 2, will determine the role of the arginine methyltransferase in regulating gene expression, Hedgehog signaling, and beta cell proliferation using conditional knockout mouse models. Aim 3 will evaluate the impact of experimental therapy on MEN1 tumors by targeting Hh signaling and the CDK axis using mouse MEN1 models. Collectively, these studies will likely unravel a new paradigm for understanding how menin suppresses MEN1 tumor syndrome via crosstalk with a key transcription factor, an epigenetic regulator, and a pro-proliferative signalig pathway. As effective and clinically safe Hh signaling and CDK inhibitors have already been developed, our proposed studies will likely accelerate translation of the basic and mechanistic studies to treating MEN1 tumor syndrome and other MEN1-mutated neuroendocrine tumors with the Hh signaling and CDK inhibitors.

描述（由申请人提供）：我们的长期目标是阐明遗传性多种内分泌肿瘤1（MEN1）综合征的分子机制，并为发展新颖和改善的治疗铺平了道路。 Men1综合征的特征是多个内分泌器官中肿瘤的发展，是由Men1基因突变引起的，该突变编码了肿瘤抑制剂Menin。由于在偶发的神经内分泌肿瘤的患者中，MEN1基因也突变，因此了解Menin如何抑制Men1肿瘤可能会为MEN1肿瘤和其他零星内分泌肿瘤如何发展提供新的见解。针对MEN1综合征的有针对性疗法缺乏但非常可取。 Men1基因消融的小鼠模型紧密地表现为MEN1肿瘤综合征，作为研究人类Menin肿瘤抑制功能的可靠模型。 Menin是一种支架蛋白，具有多种功能，包括调节基因转录。梅宁的之一作用是增加抗增殖性细胞周期蛋白依赖性激酶抑制剂（CDKIS），p18和p27的表达。然而，关于梅宁是否抑制促增殖基因的表达知之甚少。我们最近的研究解决了Menin结合Jund的共结构结构，该结构是带有深口袋的转录因子Jund，并表明Menin通过抑制其磷酸化和转录活性来抑制Jund的功能。此外，在小鼠的胰岛中，急性MEN1切除引起了多种促增殖基因的表达，以及促增殖性刺猬（HH）信号通路的成分。此外，我们发现Menin直接与转录抑制组蛋白精氨酸甲基转移酶相互作用抑制与HH信号相关的基因。我们假设Menin在功能上与JUND和甲基转移酶相互作用，以抑制促增强基因的表达，以及促进刺猬信号传导的基因，并且对HH信号的药理抑制有效治疗Men1肿瘤。为了测试这些假设，AIM 1将通过调节JUND和精氨酸甲基转移酶来研究Menin表观遗传学如何控制细胞周期蛋白D1的表达，以及与梅宁调节的CDKI轴的相互作用。 AIM 2将确定精氨酸甲基转移酶在调节基因表达，刺猬信号传导和β细胞增殖中使用条件敲除小鼠模型的作用。 AIM 3将使用小鼠MEN1模型靶向HH信号传导和CDK轴来评估实验疗法对MEN1肿瘤的影响。总的来说，这些研究可能会揭示一个新的范式，以了解Menin如何通过与关键转录因子，表观遗传调节剂和促增殖性信号途径抑制Men1肿瘤综合征。由于已经开发出有效和临床安全的HH信号和CDK抑制剂，我们提出的研究可能会加速使用HH信号和CDK抑制剂的MEN1肿瘤综合征和其他MEN1肿瘤神经内分泌肿瘤的基本和机械研究。