title: Bortezomib induction of C/EBPβ mediates Epstein-Barr virus lytic activation in Burkitt lymphoma.
abstract: Epstein-Barr virus (EBV) is associated with a variety of lymphoid malignancies. Bortezomib activates EBV lytic gene expression. Bortezomib, a proteasome inhibitor, leads to increased levels of CCAAT/enhancer-binding proteinβ (C/EBPβ) in a variety of tumor cell lines. C/EBPβ activates the promoter of the EBV lytic switch gene ZTA. Bortezomib treatment leads to increased binding of C/EBP to previously recognized binding sites in the ZTA promoter. Knockdown of C/EBPβ inhibits bortezomib activation of EBV lytic gene expression. Bortezomib also induces the unfolded protein response (UPR), as evidenced by increases in ATF4, CHOP10, and XBP1s and cleavage of ATF6. Thapsigargin, an inducer of the UPR that does not interfere with proteasome function, also induces EBV lytic gene expression. The effects of thapsigargin on EBV lytic gene expression are also inhibited by C/EBPβ knock-down. Therefore, C/EBPβ mediates the activation of EBV lytic gene expression associated with bortezomib and another UPR inducer.
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Courtney M
authors: CM
authors: Shirley
authors: Jianmeng
authors: J
authors: Chen
authors: Meir
authors: M
authors: Shamay
authors: Huili
authors: H
authors: Li
authors: Cynthia A
authors: CA
authors: Zahnow
authors: S Diane
authors: SD
authors: Hayward
authors: Richard F
authors: RF
authors: Ambinder
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D020218:Response Elements; D019284:Thapsigargin / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D000071717:X-Box Binding Protein 1
chemical_list: C497109:ATF4 protein, human; C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents; C063676:BZLF1 protein, Herpesvirus 4, Human; D001897:Boronic Acids; D022782:CCAAT-Enhancer-Binding Protein-beta; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D019284:Thapsigargin; D000069286:Bortezomib