Regulation of Nuclear Signaling Pathways by the Adenovirus E4 ORF3 Protein

腺病毒 E4 ORF3 蛋白对核信号通路的调节

• 批准号: 7405395
• 负责人: PATRICK HEARING
• 金额: $ 32.75万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405395
• 关键词: Acute Promyelocytic Leukemia; Adenovirus Infections; Adenoviruses; Apoptosis; Binding; Cancerous; Cell Differentiation process; Cell Nucleus; Cell physiology; Cells; Chimeric Proteins; Complex; Coupled; DNA Damage; DNA Repair; DNA Repair Pathway; DNA Sequence Rearrangement; DNA Viruses; DNA biosynthesis; Disease remission; Gene Expression; Goals; Human; Human Development; Interferons; Leukemic Cell; Life; Link; Localized; Malignant Neoplasms; Mediating; Molecular Probes; Myeloid Cells; Nuclear; Nuclear Protein; Nuclear Proteins; Nuclear Structure; Oncogenic; Patients; Process; Proteins; Proteomics; RARA gene; Range; Reciprocal Translocation; Regulation; Role; Signal Pathway; Signal Transduction; Structure; Time; Transcriptional Regulation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Viral; Virus; Virus Diseases; base; cell growth; cellular imaging; insight; protein structure function; repaired; response; retinoic acid receptor alpha; sensor; transcription factor; transcriptional intermediary factor 1; tumor

DESCRIPTION (provided by applicant): Reciprocal translocation of the PML tumor suppressor gene and retinoic acid receptor alpha gene is found in nearly all cases of human acute promyelocytic leukemia (APL). The PML-RAR-alpha fusion protein lacks PML tumor suppressor activity and blocks RAR-alpha-induced myeloid cell differentiation, resulting in the cancerous expansion of myeloid cell precursors. Normally, the PML protein is localized within discrete nuclear structures referred to as PML nuclear bodies, PML oncogenic domains (PODs), or ND10. PODs are disrupted in the nuclei of leukemic cells from patients with APL. During disease remission, normal POD structures reform. These results, and others, indicate that deregulation of PML activity may be linked to a variety of human malignancies. PODs are dynamic structures, and the PML protein has been implicated in a variety of important cellular processes including transcriptional regulation, cellular growth control, repair of DNA damage, apoptosis, and response to interferon. PML nuclear bodies are targets of DNA viruses. The adenovirus (Ad) E4 ORF3 protein is necessary and sufficient to mediate the reorganization of PML nuclear bodies, and associated components, into track-like structures early during viral infection. Ad E4 ORF3 also directs the relocalization of nuclear proteins involved in a cellular DNA damage response to Ad infection including Mre11, RadSO and Nbs1 (the MRN complex). E4 ORF3 inhibits MRN activity to block DNA repair pathways that interfere with Ad DNA replication. The E4 ORF3 protein directly binds to and relocalizes the transcriptional regulator TIF1 alpha. The functional consequences of TIF1 alpha interaction with E4 ORF3 are unknown, but may influence viral and/or cellular gene expression, or the ability of E4 ORF3 to reorganize PML or MRN proteins during viral infection. Finally, we have shown that Ad E4 ORF3 abrogates an interferon response during viral infection and this function may involve PML. Our goals are to understand how the different functions of the Ad E4 ORF3 protein may be related to each other and the underlying mechanisms of E4 ORF3 protein activity. The elucidation of Ad E4 ORF3 functions is expected to provide unique insight into the function of PML oncogenic domains, whose deregulation are linked to the development of human cancers, as well as the regulation of different cellular effectors and cellular responses during viral infection.

描述（由申请人提供）：几乎所有人类急性早幼粒细胞白血病（APL）病例中都发现了PML肿瘤抑制基因和视黄酸受体α基因的相互易位。 PML-RAR-α融合蛋白缺乏PML肿瘤抑制活性，并阻断RAR-α诱导的骨髓细胞分化，导致骨髓细胞前体癌性扩张。通常，PML 蛋白位于离散的核结构内，称为 PML 核体、PML 致癌结构域 (POD) 或 ND10。 APL 患者白血病细胞的细胞核中的 POD 被破坏。在疾病缓解期间，正常的 POD 结构会发生改变。这些结果和其他结果表明，PML 活性的失调可能与多种人类恶性肿瘤有关。 POD 是动态结构，PML 蛋白参与多种重要的细胞过程，包括转录调节、细胞生长控制、DNA 损伤修复、细胞凋亡和对干扰素的反应。 PML 核体是 DNA 病毒的目标。腺病毒 (Ad) E4 ORF3 蛋白对于介导 PML 核体和相关成分在病毒感染早期重组为轨道状结构是必要且充分的。 Ad E4 ORF3 还指导参与 Ad 感染的细胞 DNA 损伤反应的核蛋白的重新定位，包括 Mre11、RadSO 和 Nbs1（MRN 复合物）。 E4 ORF3 抑制 MRN 活性，从而阻断干扰 Ad DNA 复制的 DNA 修复途径。 E4 ORF3 蛋白直接结合并重新定位转录调节因子 TIF1 α。 TIF1 α 与 E4 ORF3 相互作用的功能后果尚不清楚，但可能会影响病毒和/或细胞基因表达，或 E4 ORF3 在病毒感染期间重组 PML 或 MRN 蛋白的能力。最后，我们发现 Ad E4 ORF3 在病毒感染期间消除干扰素反应，并且该功能可能涉及 PML。我们的目标是了解 Ad E4 ORF3 蛋白的不同功能如何相互关联以及 E4 ORF3 蛋白活性的潜在机制。 Ad E4 ORF3功能的阐明有望为PML致癌结构域的功能提供独特的见解，其失调与人类癌症的发展以及病毒感染期间不同细胞效应器和细胞反应的调节有关。