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The Epstein‐Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP‐10: Importance of mRNA half‐life regulation
Author(s) -
Vockerodt Martina,
Pinkert Diana,
SmolaHess Sigrun,
Michels Astrid,
Ransohoff Richard M.,
Tesch Hans,
Kube Dieter
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20759
Subject(s) - microbiology and biotechnology , biology , messenger rna , signal transduction , regulation of gene expression , p38 mitogen activated protein kinases , chemokine , gene , chemistry , receptor , mapk/erk pathway , genetics
The latent membrane protein 1 (LMP1) of Epstein‐Barr Virus (EBV) is the main inducer of immuno‐modulatory molecules affecting growth and survival of EBV‐infected cells. However, the network of signalling pathways involved remains to be elucidated. Here we show that LMP1 may regulate cellular genes like IFN‐γ‐inducible protein‐10 kDa (IP‐10) not only through transcriptional but also post‐transcriptional mechanisms. LMP1‐mediated IP‐10 expression is independent from IFN‐γ, TNF‐α or IL‐18. Transcriptional activation of IP‐10 by LMP1 or CD40 stimulation depends on an NF‐κB motif within the proximal 435 bp fragment. Carboxy‐terminal activating regions 1 or 2 of LMP1 are sufficient to direct IP‐10 promoter activation. IP‐10 induction is inhibited by blockade of p38/SAPK2 with SB 202190, which results in decreased IP‐10 mRNA half‐life without affecting IP‐10 promoter activity. Thus, LMP1‐mediated p38/SAPK2 activation regulates transcript stability. This new mechanism of gene regulation demonstrates the potential of the oncoprotein LMP1 to orchestrate a network of signalling pathways at different regulatory levels including mRNA stability. © 2004 Wiley‐Liss, Inc.