Regulation of Nuclear Signaling Pathways by the Adenovirus E4 ORF3 Protein

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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.