A NOVEL NUCLEAR STRUCTURE THAT SILENCES P53 ACTIVITY

一种抑制 P53 活性的新型核结构

• 批准号: 8361942
• 负责人: Clodagh O'Shea
• 金额: $ 2.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361942
• 关键词: Adenoviruses; Biochemical; Cell Proliferation; Cell Survival; Chromatin; Collaborations; DNA Tumor Viruses; DNA Viruses; Epigenetic Process; Funding; Goals; Grant; Heterochromatin; Human; Image Analysis; MDM2 gene; Malignant Neoplasms; Mediating; Molecular; Mutation; National Center for Research Resources; Nuclear Matrix; Nuclear Structure; Pathway interactions; Phosphorylation; Principal Investigator; Research; Research Infrastructure; Resources; Role; Source; Structure; TP53 gene; Tumor Suppressor Genes; United States National Institutes of Health; Viral; Viral Proteins; cell growth; cellular targeting; cost; insight; novel; promoter; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tumor mutations and small DNA tumor virus proteins converge in deregulating many of the same critical cellular targets and mechanisms to drive aberrant cell proliferation. Many of the critical insights into key oncogenes and tumor suppressors pathways were first identified in studies of the small DNA tumor virus proteins. Thus, viral proteins are powerful biochemical probes to define novel cellular targets that are deregulated in cancer. Studies with DNA virus proteins have elucidated many of the critical targets and mechansims that regulate cell growth and survival and which are disrupted in human cancer, such as, p53. The degradation of p53 by cellular MDM2 and Adenovirus E1B-55k is thought to be critical for p53 inactivation in cellular and viral replication, respectively. However, recent studies from the O'Shea lab have revealed a viral protein that acts via a novel and dominant epigenetic mechanism to silence p53 activity at cellular chromatin, irrespective of p53 stabilization and phosphorylation. The de novo induction of repressive heterochromatin at p53 responsive promoters is associated with the formation of a novel nuclear matrix like structure. In collaboration with the NCMIR, the goal of this project is to elucidate the molecular features and role of this novel nuclear structure in mediating heterochromatin formation and p53 inactivation in viral and tumor replication.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 肿瘤突变和小型DNA肿瘤病毒蛋白会汇聚，以消除许多相同的关键细胞靶标和机制，以驱动异常细胞增殖。 在小型DNA肿瘤病毒蛋白的研究中，首先发现了对关键致癌基因和肿瘤抑制器途径的许多关键见解。 因此，病毒蛋白是强大的生化探针，用于定义在癌症中失控的新细胞靶标。 对DNA病毒蛋白的研究已经阐明了许多调节细胞生长和存活并在人类癌症中受到破坏的关键靶标和机甲，例如p53。细胞MDM2和腺病毒E1B-55K对p53的降解被认为对p53分别在细胞和病毒复制中分别至关重要。然而，来自O'Shea实验室的最新研究揭示了一种病毒蛋白，该病毒蛋白通过一种新颖的和主导的表观遗传学机制起作用，以使p53活性在细胞染色质上静音，而与p53稳定和磷酸化无关。从p53响应启动子处的抑制性异染色质从头诱导与新型核基质类似结构的形成有关。与NCMIR合作，该项目的目的是阐明这种新型核结构在介导异染色质形成和p53在病毒和肿瘤复制中的失活的分子特征和作用。