DOWNREGULATION OF P53 PROTEIN BY KSHV VIRF1

KSHV VIRF1 下调 P53 蛋白

• 批准号: 7562089
• 负责人: YOUNG cheol SHIN
• 金额: $ 5.8万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562089
• 关键词: Apoptosis; Biochemical; Cell Cycle Arrest; Cells; Computer Retrieval of Information on Scientific Projects Database; DNA Binding Domain; DNA Damage; Down-Regulation; Funding; Grant; Human Herpesvirus 8; Institution; Mediating; Medical Surveillance; Natural Immunity; Nuclear Export; Phosphorylation; Phosphotransferases; Protein p53; Proteins; Research; Research Personnel; Resources; Serine; Signal Transduction Pathway; Source; Stress; TP53 gene; Transactivation; Transcriptional Activation; Ubiquitination; United States National Institutes of Health; Viral; Virus; ataxia telangiectasia mutated protein; multicatalytic endopeptidase complex; response; viral interferon regulatory factor-1

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Infected cells recognize viral replication as a DNA damage stress and elicit ataxia telangiectasia-mutated (ATM)/p53-mediated DNA damage response signal transduction pathway as part of the host surveillance mechanisms, which ultimately induces the irreversible cell cycle arrest and apoptosis. Virus has evolved a variety of mechanisms to counteract this host intracellular innate immunity. Kaposi's Sarcoma-Associated Herpesvirus (KSHV) viral interferon regulatory factor 1 (vIRF1) interacts with cellular p53 tumor suppressor through its central DNA binding domain and this interaction inhibits transcriptional activation of p53. Here, we further demonstrate that KSHV vIRF1 downregulates total p53 protein level by facilitating its proteasome-mediated degradation. Detailed biochemical study showed that vIRF1 interacted with cellular ATM kinase through its carboxyl terminal transactivation domain, and that this interaction blocked the activation of ATM kinase activity induced by DNA damage stress. As a consequence, vIRF1 expression greatly reduced the level of the serine 15 phosphorylation of p53, resulting the increase of p53 ubiquitination and nuclear export and thereby, the decrease of its protein stability.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 感染细胞将病毒复制识别为DNA损伤应激，并引发共济失调毛细血管扩张突变（ATM）/p53介导的DNA损伤反应信号转导通路，作为宿主监视机制的一部分，最终诱导不可逆的细胞周期阻滞和凋亡。病毒已经进化出多种机制来对抗这种宿主的细胞内先天免疫。卡波西肉瘤相关疱疹病毒（KSHV）病毒干扰素调节因子1（vIRF 1）通过其中心DNA结合结构域与细胞p53肿瘤抑制因子相互作用，这种相互作用抑制p53的转录激活。在这里，我们进一步证明，KSHV vIRF 1下调总p53蛋白水平，促进其蛋白酶体介导的降解。详细的生化研究表明，vIRF 1通过其羧基端反式激活结构域与细胞ATM激酶相互作用，这种相互作用阻断了DNA损伤应激诱导的ATM激酶活性的激活。因此，vIRF 1表达大大降低了p53的丝氨酸15磷酸化水平，导致p53泛素化和核输出增加，从而降低其蛋白质稳定性。