Genome maintenance functions of CREB/ATF transcription factors

CREB/ATF转录因子的基因组维持功能

基本信息

批准号：
8737817
负责人：
Randal Scot Tibbetts
金额：
$ 26.94万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737817
关键词：
ATM gene ATM wt Allele Acetylation Alleles Animal Model Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase Binding Proteins Biological Assay Brain CREB-binding protein Calcium Cell model Chromatin Chronic Complex Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein DNA DNA Damage DNA Double Strand Break DNA Repair DNA-dependent protein kinase Defect Development Double Strand Break Repair Down-Regulation EP300 gene Environment Exhibits Family Gene Expression Gene Expression Profile Gene Targeting Genetic Genetic Transcription Genome Genomic Instability Genomics Genotoxic Stress Glucagon Gluconeogenesis Goals Growth Factor Histone Acetylation Histones Housekeeping Housekeeping Gene Human In Vitro Lasers Leucine Zippers Long-Term Potentiation Maintenance Malignant Neoplasms Measures Mediating Memory Metabolic Metabolism Modeling Molecular Mus Mutagens Mutation Nucleosomes Oncogenic Pathway interactions Phosphorylation Physiological Play Poly(ADP-ribose) Polymerases Predisposition Protein Binding Protein Family Protein p53 Proteins Radiation Recruitment Activity Regulation Resistance Response Elements Role Site Stress Sum Synapses Synaptic plasticity Syndrome Testing Textbooks Tissues Transactivation Transcriptional Regulation Transferase Tumor Suppression Tumor Suppressor Proteins Work activating transcription factor activating transcription factor 1 ataxia telangiectasia mutated protein bZIP Domain base casein kinase I common cellular transcription factor ATF human CREBBP protein in vivo loss of function member novel overexpression programs protein function public health relevance research study response transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The overarching goal of this study is to define novel roles for CREB/ATF transcription factors in genome protection. Members of the CREB (cAMP response element-binding protein) family, including CREB, CREM, and ATF1, mediate transcriptional response to cAMP, calcium, and growth factors. It has long been known that CREB plays an important role in the metabolic regulation-where glucagon stimulates CREB-dependent transcriptional programs that promote gluconeogenesis-and the brain, where CREB promotes synaptic long-term potentiation and memory formation. For the past several years, our group has been studying CREB in the noncanonical context of DNA damage. We discovered that CREB is regulated by the ATM (ataxia-telangiectasia-mutated) protein kinase, which is a tumor suppressor protein that functions as master regulator of the DNA damage response (DDR). ATM phosphorylates CREB on a highly conserved cluster of Ser/Thr residues, within the CREB transactivation domain termed the ATM/CK cluster. Phosphorylation of the ATM/CK cluster antagonizes CREB transcriptional functions in vitro; however, the physiologic ramifications of CREB phosphorylation in vivo have not been established. To ascertain the functional importance of ATM-CREB regulation during the DDR, we generated CREB gene targeted mice (CREBS111A/S111A) encoding a CREB protein that is resistant to phosphorylation by ATM. Tissues from CREBS111A/S111A mice show constitutively elevated CREB activity that is resistant to downregulation by DNA damage. We will now use the CREBS111A/S111A model to test our major hypothesis that ATM-mediated CREB phosphorylation is required for downregulation of CREB transcriptional programs and tumor suppression. A key aspect of these studies is to test whether the ATM-CREB pathway synergizes with a parallel ATM-p53 pathway to mediate tumor suppression in vivo. Finally, even though CREB is best known for regulating gene expression, we recently discovered that CREB is unexpectedly recruited to sites of DNA damage. One exciting idea to emerge from this finding is that CREB harbors a novel function in DNA double-strand break repair that might be regulated by ATM. Experiments outlined in this study will test this hypothesis, which has implications for genome protection and tumor suppression. In sum, our studies will define new functions for CREB family transcription factors in genome protection. The Specific Aims of the proposal are to: (i) Characterize gene expression mechanisms in CREBS111A/S111A mice; (ii) Elucidate mechanisms and functional consequences of CREB recruitment to DNA damage; and (iii) Test whether CREBS111A/S111A mice manifest genome instability.

描述（由申请人提供）：本研究的总体目标是确定 CREB/ATF 转录因子在基因组保护中的新作用。 CREB（cAMP 反应元件结合蛋白）家族的成员，包括 CREB、CREM 和 ATF1，介导对 cAMP、钙和生长因子的转录反应。人们早就知道，CREB 在代谢调节（胰高血糖素刺激 CREB 依赖性转录程序，促进糖异生）和大脑中发挥着重要作用，在大脑中，CREB 促进突触长期增强和记忆形成。在过去的几年里，我们的小组一直在 DNA 损伤的非典型背景下研究 CREB。我们发现 CREB 受到 ATM（共济失调毛细血管扩张突变）蛋白激酶的调节，ATM 蛋白激酶是一种肿瘤抑制蛋白，充当 DNA 损伤反应 (DDR) 的主调节因子。 ATM 在高度保守的 Ser/Thr 残基簇上磷酸化 CREB，该簇位于 CREB 反式激活结构域（称为 ATM/CK 簇）内。 ATM/CK 簇的磷酸化在体外拮抗 CREB 转录功能；然而，CREB 磷酸化在体内的生理影响尚未确定。为了确定 DDR 期间 ATM-CREB 调节的功能重要性，我们培育了编码 CREB 蛋白的 CREB 基因靶向小鼠 (CREBS111A/S111A)，该蛋白可抵抗 ATM 磷酸化。 CREBS111A/S111A 小鼠的组织表现出持续升高的 CREB 活性，并且能够抵抗 DNA 损伤导致的下调。我们现在将使用 CREBS111A/S111A 模型来检验我们的主要假设，即 ATM 介导的 CREB 磷酸化是 CREB 转录程序下调和肿瘤抑制所必需的。这些研究的一个关键方面是测试 ATM-CREB 通路是否与平行的 ATM-p53 通路协同作用以介导体内肿瘤抑制。最后，尽管 CREB 以调节基因表达而闻名，但我们最近发现 CREB 意外地被招募到 DNA 损伤位点。从这一发现中得出的一个令人兴奋的想法是，CREB 在 DNA 双链断裂修复中具有一种新功能，该功能可能受到 ATM 的调节。本研究中概述的实验将检验这一假设，该假设对基因组保护和肿瘤抑制具有影响。总之，我们的研究将定义 CREB 家族转录因子在基因组保护中的新功能。该提案的具体目标是： (i) 表征 CREBS111A/S111A 小鼠的基因表达机制； (ii) 阐明 CREB 募集对 DNA 损伤的机制和功能后果； (iii)测试CREBS111A/S111A小鼠是否表现出基因组不稳定。