Regulation of Nuclear Signaling Pathways by the Adenovirus E4 ORF3 Protein

描述（申请人提供）：几乎在所有人类急性早幼粒细胞白血病（APL）病例中均发现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诱导的髓样细胞分化，导致髓样细胞前体的癌性扩增。通常，PML蛋白定位于称为PML核体、PML致癌结构域（POD）或ND 10的离散核结构内。POD在APL患者的白血病细胞的细胞核中被破坏。在疾病缓解期间，正常POD结构改革。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应答。PML核小体是DNA病毒的靶点。腺病毒（Ad）E4 ORF 3蛋白在病毒感染早期介导PML核体和相关组分重组为轨道样结构是必要且充分的。Ad E4 ORF 3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Mre 11，RadSO和Nbs 1（MRN复合物）。E4 ORF 3抑制MRN活性以阻断干扰Ad DNA复制的DNA修复途径。E4 ORF 3蛋白直接结合并重新定位转录调节因子TIF 1 α。TIF 1 α与E4 ORF 3相互作用的功能后果尚不清楚，但可能影响病毒和/或细胞基因表达，或E4 ORF 3在病毒感染期间重组PML或MRN蛋白的能力。最后，我们已经表明，Ad E4 ORF 3废除病毒感染期间的干扰素反应，这一功能可能涉及PML。我们的目标是了解如何不同的功能的Ad E4 ORF 3蛋白可能相互关联和E4 ORF 3蛋白活性的潜在机制。对Ad E4 ORF 3功能的阐明有望为PML致癌结构域的功能提供独特的见解，PML致癌结构域的失调与人类癌症的发展以及病毒感染期间不同细胞效应子和细胞应答的调节有关。

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.