CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr Virus-encoded LMP1: involvement of TRAF3 as a common mediator.
CD40, a member of the tumour necrosis factor receptor family, is expressed on the surface of B lymphocytes where its ligation provides a potent survival signal. CD40 is also expressed in basal epithelial cells and in a number of different carcinomas where its function remains unknown. We observed that contrary to the studies in normal B cells, CD40 ligation in carcinoma cell lines and in normal primary epithelial cells resulted in growth inhibition and enhanced susceptibility to apoptosis induced by anti-neoplastic drugs, TNF-alpha, Fas and ceramide. This effect was also observed in CD40-transfected Rat-1 fibroblasts. The expression of Bcl-2 did not affect growth inhibition induced by CD40 ligation in epithelial cells but the Epstein - Barr Virus-encoded latent membrane protein 1 (LMP1) blocked the effect. Whilst transient expression of LMP-1 resulted in the inhibition of epithelial cell growth, this effect was not observed with a LMP1 mutant lacking the binding domain for TRAF3, a protein which may mediate signal transduction by interacting with the cytoplasmic domains of both CD40 and LMP1. Transient expression of TRAF3 also inhibited epithelial cell growth, whilst expression of a dominant-negative TRAF3 partially blocked the inhibitory effect of CD40 ligation and of transient LMP1 expression. These results suggest that CD40 regulates epithelial cell growth in a manner mimicked by LMP1 and implicate TRAF3 as a common mediator in the transduction of the growth inhibitory signals generated via the CD40 and LMP1 pathways.
Eliopoulos
A G
AG
CRC Institute for Cancer Studies, The University of Birmingham Medical School, UK.
Dawson
C W
CW
Mosialos
G
G
Floettmann
J E
JE
Rowe
M
M
Armitage
R J
RJ
Dawson
J
J
Zapata
J M
JM
Kerr
D J
DJ
Wakelam
M J
MJ
Reed
J C
JC
Kieff
E
E
Young
L S
LS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D004357:Drug Synergism; D004847:Epithelial Cells; D006801:Humans; D011506:Proteins / Q000378:metabolism; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor; D014407:Tumor Cells, Cultured / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology; D014763:Viral Matrix Proteins / Q000378:metabolism*
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D014763:Viral Matrix Proteins