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: 7579153
• 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/7579153
• 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; Malignant Neoplasms; Mediating; Molecular Probes; Myeloid Cells; Nuclear; Nuclear Protein; Nuclear Proteins; Nuclear Structure; Oncogenic; Patients; Process; Proteins; Proteomics; RARA gene; 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(申请人提供)：PML肿瘤抑制基因和维甲酸受体α基因的相互易位在几乎所有的人类急性早幼粒细胞白血病(APL)病例中都被发现。PML-RAR-α融合蛋白缺乏PML肿瘤抑制活性，并阻断RAR-α诱导的髓系细胞分化，导致髓系细胞前体细胞的癌性扩张。正常情况下，PML蛋白定位于离散的核结构中，称为PML核体、PML致癌结构域(PODS)或ND10。急性早幼粒细胞白血病患者的白血病细胞核中的PODS被破坏。在疾病缓解期，正常的POD结构发生改变。这些结果和其他结果表明，PML活性的放松可能与多种人类恶性肿瘤有关。PODS是一种动态结构，PML蛋白参与了多种重要的细胞过程，包括转录调控、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病毒的靶标。腺病毒(Ad)E4 ORF3蛋白是介导PML核体及其相关成分在病毒感染早期重组为轨迹样结构所必需且足够的蛋白质。AdE4 ORF3还指导参与对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复合体)。E4 ORF3抑制MRN活性，阻断干扰Ad DNA复制的DNA修复途径。E4 ORF3蛋白直接与转录调控因子TIF1α结合并重新定位。TIF1α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/或细胞基因的表达，或E4 ORF3在病毒感染过程中重组PML或MRN蛋白的能力。最后，我们已经证明，在病毒感染过程中，Ad E4 ORF3可以消除干扰素反应，这一功能可能涉及PML。我们的目标是了解E4ORF3蛋白的不同功能是如何相互联系的，以及E4ORF3蛋白活性的潜在机制。对AdE4 ORF3功能的阐明有望为了解PML癌基因结构域的功能提供独特的见解，PML癌基因结构域的解除调控与人类癌症的发生有关，以及病毒感染过程中不同细胞效应物和细胞反应的调节。