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）：这项研究的总体目标是定义CREB/ATF转录因子在基因组保护中的新作用。 CREB（CAMP响应元素结合蛋白）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。长期以来，众所周知，CREB在代谢调节中起着重要作用 - 胰高血糖素刺激了CREB依赖性的转录程序，这些程序促进了糖异生和大脑，CREB促进突触长期增强和记忆形成。在过去的几年中，我们的小组一直在DNA损伤的非规范背景下研究CREB。我们发现CREB由ATM（thaxia-telangioctasia-mutated）蛋白激酶调节，这是一种肿瘤抑制蛋白，可作为DNA损伤反应（DDR）的主要调节剂。 ATM将CREB磷酸化在高度保守的SER/THR残基簇上，在CREB反式激活域中称为ATM/CK群集。 ATM/CK簇的磷酸化在体外拮抗CREB转录功能；但是，尚未确定体内CREB磷酸化的生理分析。为了确定DDR期间ATM-CREB调节的功能重要性，我们生成了CREB基因靶向小鼠（CREBS111A/S111A），编码了ATM抗磷酸化的CREB蛋白。来自Crebs11a/S111a小鼠的组织表现出组成型升高的CREB活性，这通过DNA损伤对下调具有抗性。现在，我们将使用CREBS11A/S111A模型来检验我们的主要假设，即在下调CREB转录程序和抑制肿瘤需要ATM介导的CREB磷酸化需要。这些研究的一个关键方面是测试ATM-CREB途径是否与平行的ATM-P53途径协同介导体内肿瘤抑制。最后，尽管Creb以调节基因表达而闻名，但我们最近发现CREB意外地招募到DNA损伤部位。从这一发现中得出的一个令人兴奋的想法是，Creb拥有可能由ATM调节的DNA双链休息修复中的新功能。这项研究中概述的实验将检验该假设，这对基因组保护和抑制具有影响。总而言之，我们的研究将定义基因组保护中CREB家族转录因子的新功能。该提案的具体目的是：（i）表征Crebs11a/s111a小鼠中的基因表达机制；（ii）阐明CREB募集到DNA损伤的机制和功能后果；（iii）测试Crebs11a/s111a小鼠是否表现出基因组不稳定性。