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PMID: 9009275 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member.

The EMBO journal ·Vol. 16 ·No. 1 ·1997-01-02 ·Pages 143-53

Liu S, Liu P, Borras A, Chatila T, Speck SH

Abstract

Induction of the Epstein-Barr virus (EBV) lytic cycle by crosslinking surface immunoglobulin is inhibited by the immunosuppressants cyclosporin A (CsA) and FK506. This correlates with the ability of CsA to inhibit Ca2+-dependent transcription of the lytic cycle switch gene BZLF1. It is shown here that CsA sensitivity maps to three sites (ZIA, ZIB and ZID) that bind the serum response factor-related protein MEF2D. A synthetic promoter containing multiple copies of a MEF2D site from Zp, in conjunction with a CREB/AP-1 site (ZII) from Zp, exhibits CsA-sensitive inducibility. Furthermore, the Zp MEF2D sites were functionally interchangeable with MEF2 sites derived from heterologous promoters. While no evidence of a NFAT family member binding to either the MEF2 or CREB/AP-1 sites was obtained, it could be demonstrated that CsA-sensitive induction of Zp was mediated by calcineurin and NFATc2 in synergy with either phorbol ester or especially with the EBV-induced Ca2+/calmodulin-dependent kinase type IV/Gr. These studies identify Zp as prototypic of a novel class of CsA-sensitive and NFAT-dependent promoters defined by the presence of MEF2 sites.

MeSH Terms
Binding Sites Calcineurin Calcium/metabolism Calmodulin-Binding Proteins/metabolism Cyclosporine/pharmacology DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation, Viral/drug effects,genetics Herpesvirus 4, Human/drug effects,physiology Immunosuppressive Agents/pharmacology MEF2 Transcription Factors Myogenic Regulatory Factors NFATC Transcription Factors Nuclear Proteins Phosphoprotein Phosphatases/metabolism Promoter Regions, Genetic Signal Transduction Trans-Activators/genetics Transcription Factor AP-1/metabolism Transcription Factors/metabolism Tumor Cells, Cultured Viral Proteins/genetics Virus Activation/drug effects
Chemicals
BZLF1 protein, Herpesvirus 4, Human Calmodulin-Binding Proteins DNA-Binding Proteins Immunosuppressive Agents MEF2 Transcription Factors Myogenic Regulatory Factors NFATC Transcription Factors Nuclear Proteins Trans-Activators Transcription Factor AP-1 Transcription Factors Viral Proteins Cyclosporine Calcineurin Phosphoprotein Phosphatases Calcium
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Liu S
Department of Pathology, Children's Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA.
Liu P
Borras A
Chatila T
Speck S H
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/16.1.143
Published
1997-01-02
Pages
143-53
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1169621
Subset
IM
Grants
NIAID NIH HHS · AI30550 · United States
NCI NIH HHS · CA52004 · United States
External Links
PubMed source DOI: 10.1093/emboj/16.1.143 PMC Full Text View journal details
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