Abstract:
:We previously reported that the cellular transcription factor hypoxia-inducible factor 1α (HIF-1α) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) latent-lytic switch BZLF1 gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN-4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592]). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1α and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1α failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1α to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of BZLF1 gene expression by HIF-1α requires phosphorylated, wild-type p53 as a coactivator, with HIF-1α binding recruiting p53 to Zp.IMPORTANCE EBV, a human herpesvirus, is latently present in most nasopharyngeal carcinomas, Burkitt lymphomas, and some gastric cancers. To develop a lytic-induction therapy for treating patients with EBV-associated cancers, we need a way to efficiently reactivate EBV into lytic replication. EBV's BZLF1 gene product, Zta, usually controls this reactivation switch. We previously showed that HIF-1α binds the BZLF1 gene promoter, inducing Zta synthesis, and HIF-1α-stabilizing drugs can induce EBV reactivation. In this study, we determined which EBV-positive cell lines are reactivated by classes of HIF-1α-stabilizing drugs. We found, unexpectedly, that HIF-1α-stabilizing drugs only induce reactivation when they also induce accumulation of phosphorylated, wild-type p53. Fortunately, p53 phosphorylation can also be provided by drugs such as nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.
journal_name
J Viroljournal_title
Journal of virologyauthors
Kraus RJ,Cordes BA,Sathiamoorthi S,Patel P,Yuan X,Iempridee T,Yu X,Lee DL,Lambert PF,Mertz JEdoi
10.1128/JVI.00722-20subject
Has Abstractpub_date
2020-08-31 00:00:00issue
18eissn
0022-538Xissn
1098-5514pii
JVI.00722-20journal_volume
94pub_type
杂志文章abstract::The four major Epstein-Barr virion envelope components were separated by column chromatography and reconstituted into artificial liposomes. These liposomes were tested for their ability to bind selectively to Epstein-Barr virus receptor-positive cells. Only when the two high-molecular-weight glycoproteins, VE1 and VE2...
journal_title:Journal of virology
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doi:10.1128/JVI.41.1.286-297.1982
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pub_type: 杂志文章
doi:10.1128/JVI.69.12.7622-7629.1995
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pub_type: 杂志文章
doi:10.1128/JVI.68.8.5100-5107.1994
更新日期:1994-08-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
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abstract::Crucial steps in high-risk human papillomavirus (HR-HPV)-related carcinogenesis are the integration of HR-HPV into the host genome and loss of viral episomes. The mechanisms that promote cervical neoplastic progression are, however, not clearly understood. During HR-HPV infection, the HPV E5 protein is expressed in pr...
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.5.3042-3047.1992
更新日期:1992-05-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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pub_type: 临床试验,杂志文章
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更新日期:1994-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.9.5850-5856.2005
更新日期:2005-05-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1998-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01719-08
更新日期:2009-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2019-02-05 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.12.7926-7932.2005
更新日期:2005-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.54.3.894-898.1985
更新日期:1985-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.9.2929-2933.1987
更新日期:1987-09-01 00:00:00
abstract::It has been shown previously in the severe acute respiratory syndrome coronavirus (SARS-CoV) that two point mutations, N15A and V25F, in the transmembrane domain (TMD) of the envelope (E) protein abolished channel activity and led to in vivo attenuation. Pathogenicity was recovered in mutants that also regained E prot...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02158-16
更新日期:2017-02-14 00:00:00
abstract::Productive infection by the murine autonomous parvovirus minute virus of mice (MVM) depends on a dividing cell population and its differentiation state. We have extended the in vivo analysis of the MVM host cell type range into the developing embryo by in utero inoculation followed by further gestation. The fibrotropi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.17.9474-9486.2004
更新日期:2004-09-01 00:00:00