Latent membrane protein 1-induced EGFR signalling is negatively regulated by TGF[alpha] prior to neoplasia

• Published in: Carcinogenesis (New York) Vol. 28; no. 8; p. 1839
• Main Authors: Charalambous, Chrystalla T, Hannigan, Adele, Tsimbouri, Penelope, McPhee, Gordon M, Wilson, Joanna B
• Format: Journal Article
• Language: English
• Published: Oxford Oxford Publishing Limited (England) 01.08.2007
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgm055

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is an oncoprotein 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 (transforming growth factor α (TGFα), heparin-binding EGF-like growth factor and epiregulin) 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 p38 mitogen-activated protein kinase (MAPK). Surprisingly, removal of TGFα (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 MAPK/ERK kinase (MEK) and extracellular-signal-regulated kinase (ERK) are initially activated in the null background, suggesting that TGFα or excess of the ligands together act to divert phosphorylated EGFR into a cleavage pathway. In addition, LMP1 leads to the activation of c-Jun N-terminal kinase 2 (JNK2) followed by JNK1 in the effected tissue. Specific AP1 family members FosB, Fra-1 and JunB are constitutively induced and serum response factor, AP1 and nuclear factor κB (incorporating p65) are activated in the transgenic tissue compared with 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.