E1A Oncoprotein Induced Deregulation of Replication Origin Firing

E1A癌蛋白诱导复制起点激发失调

基本信息

批准号：
8095862
负责人：
BAYAR THIMMAPAYA
金额：
$ 22.88万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8095862
关键词：
Adenoviruses Binding Binding Sites Cell Cycle Progression Cells Chromatin Complex DNA Damage DNA Synthesis Induction DNA biosynthesis DNA replication origin Down-Regulation E1A-associated p300 protein EP300 gene Family G0 Phase Gene Expression Genes Genetic Transcription Growth HDAC3 gene Histone Deacetylase Human Development In Vitro Licensing Factor Light Link Lytic Phase Macrophage-1 Antigen Malignant Neoplasms Mediating Modeling Molecular N-terminal Neoplastic Cell Transformation Oncogene Proteins Oncogenes Open Reading Frames Paper Pathway interactions Pre-Replication Complex Protein Binding Protein Family Proteins RNA Splicing Replication Origin Reporting Retinoblastoma Protein Rodent Role Running S Phase S Phase Arrest Subgroup Time Transactivation Transcription Coactivator Transforming Growth Factors Viral Virus YY1 Transcription Factor base c-myc Genes cell growth cell transformation genetic regulatory protein histone deacetylase 3 metaplastic cell transformation mutant polypeptide premature prevent response transcription factor

项目摘要

DESCRIPTION (provided by applicant): The focus of this application is to determine the mechanisms by which adenovirus (Ad) transforming E1A protein induces progression to S phase in quiescent cells, in a p300 binding dependent manner. In cooperation with cellular activated ras or virus encoded E1B19K or 55K proteins and by binding to p300/CBP and Rb family proteins, E1A can transform rodent cells. Interactions of E1A with p300/CBP and Rb proteins in quiescent cells result in rapid induction of S phase. While the inactivation of Rb proteins is well known to induce E2F and S phase, the contribution of E1A binding to p300 has not been thoroughly studied. Previously we showed that p300 prevents premature entry of quiescent cells into S phase by negatively regulating c-Myc. p300 cooperates with transcription factor YY1 and histone deacetylase 3 at an upstream YY1 binding site to keep c-Myc in a repressed state and that this contributes to maintaining cells in G0 phase. E1A induces c-Myc by interfering with this mechanism. Recently, we have discovered that a number of additional genes related to DNA synthesis and cell cycle progression are also repressed by p300 in quiescent cells and these genes are induced by E1A in a p300 binding dependent manner. Either downregulation of p300 by shRNAs or expression of wild type E1A but not p300 binding defective E1A mutants leads to the induction of c-Myc that is linked to rapid induction of S phase, activation of DNA damage response and S phase arrest. These cells contain increased cellular DNA replication origin activity. We now propose studies to determine how the origin activity is deregulated by E1A in a p300 binding dependent manner. These studies are expected to shed new light on E1A mediated aberrant S phase progression and its role in viral and cellular transformation. PUBLIC HEALTH RELEVANCE: Deregulation of cell growth control by a variety of mechanisms is a key step in the development of human cancer. Adenovirus encoded E1A is a time honored model oncoprotein. Understanding its effects on aberrant S phase progression will advance our understanding of how an oncogene by disrupting the growth inhibitory pathways of a cellular protein contributes to neoplastic transformation.

描述（由申请人提供）：本申请的重点是确定腺病毒（AD）转化E1A蛋白的机制，以p300的结合方式在静态细胞中诱导静态细胞的进展。与细胞活化的RAS或病毒编码的E1B19K或55K蛋白合作，并通过与P300/CBP和RB家族蛋白结合，E1A可以转化啮齿动物细胞。 E1A与静态细胞中P300/CBP和RB蛋白的相互作用导致S相快速诱导。虽然众所周知，RB蛋白的失活会诱导E2F和S相，但E1A结合对P300的贡献尚未得到彻底研究。以前，我们表明p300通过负调节c-myc来阻止静态细胞过早进入S相。 p300与上游YY1结合位点的转录因子YY1和组蛋白脱乙酰基酶3合作，以使C-MYC保持在抑制状态，这有助于在G0相中维持细胞。 E1A通过干扰这种机制诱导C-MYC。最近，我们发现静态细胞中p300抑制了许多与DNA合成和细胞周期进程相关的其他基因，并且这些基因以p300结合依赖性方式诱导。通过shRNA对p300的下调或野生型E1a的表达，而不是p300结合有缺陷的E1a突变体导致c-MYC的诱导，这与S相的快速诱导，DNA损伤响应的激活和S相倒置有关。这些细胞包含增加的细胞DNA复制起源活性。现在，我们提出的研究以确定如何以P300结合方式通过E1A放大原始活性。这些研究有望为E1A介导的异常相位进展及其在病毒和细胞转化中的作用提供新的启示。公共卫生相关性：通过多种机制对细胞生长控制的管制是人类癌症发展的关键步骤。腺病毒编码的E1A是一种时光的模型癌蛋白。了解其对异常S相进展的影响将使我们了解如何通过破坏细胞蛋白的生长抑制途径如何有助于肿瘤转化，从而提高我们对癌基因的理解。