The Role of ATF3 in the DNA Damage Response

ATF3 在 DNA 损伤反应中的作用

• 批准号: 8504744
• 负责人: Chunhong Yan
• 金额: $ 1.21万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504744
• 关键词: Acetylation; Animal Model; Animals; Apoptotic; Binding; Breeding; Cancer Etiology; Carcinogens; Cells; DNA Damage; Development; Dissection; EP300 gene; Embryo; Epigenetic Process; Face; Feedback; Gene Expression; Gene Mutation; Genes; Genetic Engineering; Genomics; Goals; Immediate-Early Genes; Impairment; Knockout Mice; Knowledge; Lead; Link; MDM2 gene; Malignant Neoplasms; Mediating; Molecular; Mus; Mutation; Oncogenic; Outcome; Pathway interactions; Predisposition; Preventive; Protein p53; Proteins; Recruitment Activity; Regulation; Role; Smoke; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitination; Validation; activating transcription factor 3; base; biological adaptation to stress; cancer initiation; cancer prevention; cancer therapy; driving force; early onset; histone acetyltransferase; innovation; lung carcinogenesis; novel; promoter; public health relevance; response; sensor; transcription factor; tumor progression; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The cellular response to DNA damage is an early anti-cancer barrier that maintains the genomic integrity by activating the tumor suppressor p53. Previous studies show that ATF3, an immediate-early gene which is rapidly induced as a part of cellular response to a wide-range of DNA damage, promotes p53 activation by binding to the tumor suppressor. Whereas ATF3 expression is down-regulated in various cancers, loss of ATF3 impairs the DNA damage response and results in tumorigenesis. The goal of this proposal is to elucidate the role of ATF3 in regulation of the DNA damage response and tumor suppression with a focus on understanding of the mechanisms by which ATF3 regulates p53 activity in face of oncogenic challenges. Preliminary studies show that ATF3 regulates not only the stability but also the trans-activation activity of p53, and also discover a link of ATF3 with other p53 network proteins including E3 ubiquitin ligase MDM2 and histone acetyltransferases p300, Tip60 and hMOF. We therefore hypothesize that these interactions could be behind the mechanisms by which ATF3 regulates p53 tumor suppressor activity in the DNA damage response. In Aim #1, a hypothesis that the interaction between ATF3 and MDM2 contributes to p53 stabilization by regulating the binding of MDM2 to p53 and/or its catalytic activity towards p53 ubiquitination will be tested. In addition, we will characterize the contribution of the ATF3-MDM2 feedback loop to p53 regulation using Mdm2-knockout mice. In Aim #2, we will test a hypothesis that ATF3 regulates p53 trans-activation activity by promoting the interactions of p53 with its transcriptional co-regulators. Towards this aim, effects of ATF3 on p53 acetylation catalyzed by p300, Tip60 and hMOF, and subsequent epigenetic alterations and recruitments of transcriptional regulators that are essential for activation of p53- target gene expression will be determined. In Aim #3, we will assess the contribution of ATF3 to tumor suppression using genetically-engineered animal models. ATF3-deficient mice will also be bred and tested for its susceptibility to lung carcinogenesis induced by smoke carcinogens. Together these studies will render evidence supporting an indispensable role of ATF3 in p53-mediated DNA damage response and tumor suppression. Given that inadequate DNA damage response is a driving force for cancer initiation and progression, the fundamental new knowledge obtained from the proposed studies will establish ATF3 as a promising target for preventive and/or therapeutic treatments of cancer.

描述（由申请人提供）：对DNA损伤的细胞反应是一种早期的抗癌屏障，通过激活肿瘤抑制p53来维持基因组完整性。先前的研究表明，ATF3是一种直接至上的基因，作为对大量DNA损伤的细胞反应的一部分，它通过与肿瘤抑制剂结合而促进p53激活。而在各种癌症中ATF3表达下调，而ATF3的丧失会损害DNA损伤反应并导致肿瘤发生。该提案的目的是阐明ATF3在调节DNA损伤反应和肿瘤抑制中的作用，重点是理解ATF3在面对致癌挑战时调节p53活性的机制。初步研究表明，ATF3不仅调节稳定性，而且调节p53的反式激活活性，还发现ATF3与其他p53网络蛋白（包括E3泛素连接酶MDM2）和组蛋白乙酰转移酶P300，TIP60和HMOF的链接。因此，我们假设这些相互作用可能是ATF3在DNA损伤反应中调节p53肿瘤抑制活性的机制的背后。在AIM＃1中，通过调节MDM2与p53和/或其催化活性与p53泛素化的催化活性的结合，将测试ATF3和MDM2之间的相互作用的假设。此外，我们将使用MDM2敲除小鼠来表征ATF3-MDM2反馈回路对P53调节的贡献。在AIM＃2中，我们将检验一个假设，即ATF3通过促进p53及其转录共同调节剂的相互作用来调节p53反式激活活性。为此，将确定AT​​F3对P300，TIP60和HMOF催化的p53乙酰化的影响，以及随后确定转录调节剂的表观遗传改变和募集对于激活p53-靶基因表达至关重要的转录调节剂。在AIM＃3中，我们将使用基因工程动物模型评估ATF3对肿瘤抑制的贡献。 ATF3缺乏的小鼠还将繁殖并测试其烟雾致癌物诱导的肺癌发生的敏感性。这些研究将共同​​提供支持ATF3在p53介导的DNA损伤反应和抑制肿瘤中必不可少的作用的证据。鉴于DNA损伤反应不足是癌症开始和进展的驱动力，因此从拟议的研究中获得的基本新知识将建立ATF3作为预防和/或治疗性癌症的有希望的靶标。