title: Interplay between PKCδ and Sp1 on histone deacetylase inhibitor-mediated Epstein-Barr virus reactivation.
abstract: Epstein-Barr virus (EBV) undergoes latent and lytic replication cycles, and its reactivation from latency to lytic replication is initiated by expression of the two viral immediate-early transactivators, Zta and Rta. In vitro, reactivation of EBV can be induced by anti-immunoglobulin, tetradecanoyl phorbol acetate, and histone deacetylase inhibitor (HDACi). We have discovered that protein kinase C delta (PKCδ) is required specifically for EBV reactivation by HDACi. Overexpression of PKCδ is sufficient to induce the activity of the Zta promoter (Zp) but not of the Rta promoter (Rp). Deletion analysis revealed that the ZID element of Zp is important for PKCδ activation. Moreover, the Sp1 putative sequence on ZID is essential for PKCδ-induced Zp activity, and the physiological binding of Sp1 on ZID has been confirmed. After HDACi treatment, activated PKCδ can phosphorylate Sp1 at serine residues and might result in dissociation of the HDAC2 repressor from ZID. HDACi-mediated HDAC2-Sp1 dissociation can be inhibited by the PKCδ inhibitor, Rotterlin. Furthermore, overexpression of HDAC2 can suppress the HDACi-induced Zp activity. Consequently, we hypothesize that HDACi induces PKCδ activation, causing phosphorylation of Sp1, and that the interplay between PKCδ and Sp1 results in the release of HDAC2 repressor from Zp and initiation of Zta expression.
authors.affiliation: College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Tsai
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Lin
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Weng
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Tsai
authors.forename: Jiun-Han
authors.initials: JH
authors.lastname: Lin
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chou
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Tsai
mesh_terms: D002460:Cell Line; D020031:Epstein-Barr Virus Infections / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects*
chemical_list: C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017874:Immediate-Early Proteins; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; C012589:trichostatin A; D051745:Protein Kinase C-delta