| Upregulation of STAT3 marks Burkitt lymphoma cells refractory to Epstein-Barr virus lytic cycle induction by HDAC inhibitors. | |
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MedLine Citation:
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PMID: 19889776 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A fundamental problem in studying the latent-to-lytic switch of Epstein-Barr virus (EBV) and the viral lytic cycle itself is the lack of a culture system fully permissive to lytic cycle induction. Strategies to target EBV-positive tumors by inducing the viral lytic cycle with chemical agents are hindered by inefficient responses to stimuli. In vitro, even in the most susceptible cell lines, more than 50% of cells latently infected with EBV are refractory to induction of the lytic cycle. The mechanisms underlying the refractory state are not understood. We separated lytic from refractory Burkitt lymphoma-derived HH514-16 cells after treatment with an HDAC inhibitor, sodium butyrate. Both refractory- and lytic-cell populations responded to the inducing stimulus by hyperacetylation of histone H3. However, analysis of host cell gene expression showed that specific cellular transcripts Stat3, Fos, and interleukin-8 (IL-8) were preferentially upregulated in the refractory-cell population, while IL-6 was upregulated in the lytic population. STAT3 protein levels were also substantially increased in refractory cells relative to untreated or lytic cells. This increase in de novo expression resulted primarily in unphosphorylated STAT3. Examination of single cells revealed that high levels of STAT3 were strongly associated with the refractory state. The refractory state is manifest in a unique subpopulation of cells that exhibits different cellular responses than do lytic cells exposed to the same stimulus. Identifying characteristics of cells refractory to lytic induction relative to cells that undergo lytic activation will be an important step in developing a better understanding of the regulation of the EBV latent to lytic switch. |
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Authors:
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Derek Daigle; Cynthia Megyola; Ayman El-Guindy; Lyn Gradoville; David Tuck; George Miller; Sumita Bhaduri-McIntosh |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-11-04 |
Journal Detail:
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Title: Journal of virology Volume: 84 ISSN: 1098-5514 ISO Abbreviation: J. Virol. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-23 Completed Date: 2010-01-12 Revised Date: 2010-09-28 |
Medline Journal Info:
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Nlm Unique ID: 0113724 Medline TA: J Virol Country: United States |
Other Details:
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Languages: eng Pagination: 993-1004 Citation Subset: IM |
Affiliation:
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Department of Molecular Biophysics, Yale University School of Medicine, New Haven, Connecticut 06520, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals B-Lymphocytes* / drug effects, virology Butyrates / pharmacology Cell Line, Transformed Cell Line, Tumor Herpesvirus 4, Human / drug effects*, physiology Histone Deacetylase Inhibitors / pharmacology* Humans Rabbits STAT3 Transcription Factor / metabolism* Up-Regulation* Virus Activation / drug effects* Virus Latency |
| Grant Support | |
ID/Acronym/Agency:
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1 U24 NS051869/NS/NINDS NIH HHS; 1UL1RR024139-02/RR/NCRR NIH HHS; 5 T32 GM07223/GM/NIGMS NIH HHS; CA12055/CA/NCI NIH HHS; CA16038/CA/NCI NIH HHS; K08 AI062732/AI/NIAID NIH HHS; K12 HD001401/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Butyrates; 0/Histone Deacetylase Inhibitors; 0/STAT3 Transcription Factor |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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