Skip Navigation



Carcinogenesis Advance Access published online on March 14, 2007
Carcinogenesis, doi:10.1093/carcin/bgm055
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrowOA All Versions of this Article:
28/8/1839    most recent
bgm055v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Charalambous, C.
Right arrow Articles by Wilson, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Charalambous, C.
Right arrow Articles by Wilson, J. B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Latent membrane protein 1 induced EGFR signalling is negatively regulated by TGF{alpha} prior to neoplasia

Chrystalla Charalambous, Adele Hannigan, Gordon McPhee, Penelope Tsimbouri and Joanna B. Wilson¥

Division of Molecular Genetics, Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK

¥ To whom correspondence should be addressed. address: Division of Molecular Genetics, Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, UK. email: Joanna.Wilson{at}bio.gla.ac.uk, Tel: +141 330 5100, FAX: +141 330 4878

The latent membrane protein-1 (LMP1) of Epstein-Barr virus is an onco-protein, expressed in several EBV-associated malignancies. We have utilised mice expressing the Cao strain of LMP1 in epithelia to explore the consequences of expression in vivo, specifically the changes that occur prior to neoplasia, in the hyperplastic but degenerating tissue. Epidermal growth factor receptor (EGFR) ligands (TGF{alpha}, HB-EGF and EPR) are constitutively induced by LMP1, leading to EGFR phosphorylation but also down-regulation, degradation or turn-over, with the appearance of cleaved EGFR fragments. This is accompanied by down-regulation of Akt and activation of caspase-3 and p38MAPK. Surprisingly, removal of TGF{alpha} (using the null strain) does not ameliorate the LMP1 induced phenotype, but instead accelerates the deterioration. Consistent with this, EGFR is reduced less rapidly and MEK and ERK are initially activated in the null background, suggesting that TGF{alpha} or excess of the ligands together act to divert phosphorylated EGFR into a cleavage pathway. In addition LMP1 leads to the activation of JNK2 followed by JNK1 in the effected tissue. Specific AP1 family members FosB, Fra1 and JunB are constitutively induced and SRF, AP1 and NF-{kappa}B (incorporating p65) are activated in the transgenic tissue compared to wild type. This system allows the analysis of early events resulting from the expression of a viral oncogene with broad impact in the signalling milieu and the attempts at homeostasis in the responding tissue. It reveals what regulatory circuits are in place in a normal tissue, thus facilitating further prediction of causative events in carcinogenic progression.

Key Words: TGF{alpha} • EGFR • LMP1 • EBV • MAPK • JNK • Akt • apoptosis

Received October 5, 2006; revised February 23, 2007; accepted March 2, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.