Project 3: Oncogene Activation and DNA Damage Response-Mediated Epigenetic Changes

项目3：癌基因激活和DNA损伤反应介导的表观遗传变化

基本信息

批准号：
10132252
负责人：
John HJ Petrini
金额：
$ 35.09万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132252
关键词：
Address Apoptosis Bone Marrow Breast Cancer Model Cell Cycle Arrest Cells Chromatin Complementary DNA Complex DNA Damage Data Defect Dependence Deposition Development Disease Enzymes Epigenetic Process Epithelial Epithelial Cells Event Fatty acid glycerol esters Fetal Liver Gamma-H2AX Genes Genetic Genetic Transcription Genome Stability Genomic Instability Hematopoietic Hematopoietic Neoplasms Hepatocyte Heterochromatin Histone Deacetylase Histone H3 Histones Human Hyperplasia Impairment Lesion Light Location Maintenance Malignant Neoplasms Mediating Microscopy Molecular Chaperones Mouse Mammary Tumor Virus Mus Myeloproliferative disease Neoplasm Metastasis Neurologic Oncogene Activation Oncogenes Oncogenic Organoids Outcome Output Pathway interactions Phenotype Phosphorylation Ploidies Process Proteomics Regulation Role Signal Transduction Stress Syndrome TP53 gene Testing Therapeutic Time Tumor Suppression Wild Type Mouse arm attenuation base c-myc Genes carcinogenesis experimental study gene product implantation in vivo insight macroH2A histone mammary mammary epithelium mouse model mutant novel p19ARF p53-binding protein 1 programs repaired reproductive response small hairpin RNA tumor

项目摘要

This proposal is based on the novel finding that in addition to activating downstream components of the DNA damage response (DDR), the Mre11 complex-ATM arm of the DDR is required to activate a p53-dependent epigenetic program in response to oncogene activation. This pathway appears to parallel that governed by Ink4a-p19Arf. We will carry out quantitative analysis of the abundance and location of chromatin marks arising in response to the activation of neuT and c-myc, and assess changes in the expression of chromatin modifying enzymes in epithelial cells. To determine whether these responses are shared by hematopoietic cells, we will examine the same endpoints as well as the onset and progression of malignancy in p53-/- and Mre11ATLD1/ATLD1 bone marrow following introduction of c-myc or the Nup98-Hox9a cDNA. Finally, having defined these features of the p53-dependent epigenetic response to oncogene, we will identify enzymes that mediate this response and test the hypothesis that this p53-dependent function which requires DDR signaling is tumor suppressive. Collectively, the experiments proposed will illuminate a previously undescribed connection between p53 and the upstream components of the DDR that effects a barrier to oncogene-driven carcinogenesis. Therefore, this proposal is highly significant with the potential to provide novel mechanistic insight regarding tumor suppression by p53.

该提议基于新发现，该发现除了激活DNA的下游成分外损坏响应（DDR），需要DDR的MRE11复合体臂来激活p53依赖性表观遗传程序响应癌基因激活。该途径似乎平行于 ink4a-p19arf。我们将对出现的染色质标记的丰度和位置进行定量分析响应NET和C-MYC的激活，并评估染色质修饰的表达的变化上皮细胞中的酶。为了确定这些反应是否由造血细胞共享，我们将检查相同的终点以及p53 - / - 和mre11atld1/atld1中恶性肿瘤的发作和进展引入C-MYC或NUP98-HOX9A cDNA后的骨髓。最后，定义了这些功能在p53依赖性表观遗传反应中，我们将确定介导这种反应的酶并检验了需要DDR信号传导的p53依赖性功能的假设是抑制肿瘤的。总的来说，提出的实验将阐明p53和 DDR的上游成分影响致癌基因驱动的癌变的障碍。因此，这个提案非常重要，有可能提供有关肿瘤的新机械洞察力 p53抑制。