The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: importance of mRNA half-life regulation.
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-gamma-inducible protein-10 kDa (IP-10) not only through transcriptional but also post-transcriptional mechanisms. LMP1-mediated IP-10 expression is independent from IFN-gamma, TNF-alpha or IL-18. Transcriptional activation of IP-10 by LMP1 or CD40 stimulation depends on an NF-kappaB 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.
Vockerodt
Martina
M
Zentrum Kinderheilkunde und Jugendmedizin, Abteilung Pädiatrie I, Georg August Universität, Göttingen, Germany.
Pinkert
Diana
D
Smola-Hess
Sigrun
S
Michels
Astrid
A
Ransohoff
Richard M
RM
Tesch
Hans
H
Kube
Dieter
D
D020816:Amino Acid Motifs; D015153:Blotting, Western; D019013:CD40 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism / Q000821:virology; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014763:Viral Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020382:Interleukin-18; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D014763:Viral Matrix Proteins; D003609:Dactinomycin; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole