Epstein-Barr virus-encoded LMP2A regulates viral and cellular gene expression by modulation of the NF-kappaB transcription factor pathway.
Epstein-Barr virus (EBV)-associated malignancies display distinct patterns of virus latent gene expression that reflect the complex interplay between the virus and its host cell. In the EBV-associated epithelial tumor nasopharyngeal carcinoma (NPC), the virus-encoded latent membrane protein LMP2A is consistently expressed whereas the oncogenic LMP1 protein appears to be restricted to only a proportion of tumors. In an attempt to understand the contribution of LMP2A to the pathogenesis of NPC, we established carcinoma cell lines stably infected in vitro with either a wild-type recombinant EBV (rEBV) or a mutant rEBV in which LMP2A is deleted (rEBV-2A). An NPC-like pattern of EBV gene expression including LMP2A but not LMP1 was consistently observed in carcinoma cells infected with rEBV. However, carcinoma cells infected with rEBV-2A expressed high levels of LMP1 from the signal transducer and activator of transcription (STAT)-regulated L1-TR promoter. Consistent with this effect, basal STAT activity was reduced in rEBV-infected carcinoma cells, and this repression was relieved in the absence of LMP2A. This modulation of STAT activity correlated with the ability of LMP2A to inhibit the autocrine secretion of IL-6 from carcinoma cell lines. Exogenous IL-6 was able to induce expression of LMP1 by means of STAT3 activation both in rEBV-infected carcinoma cell lines and in the EBV-positive C666-1 NPC cell line. The LMP2A-mediated suppression of IL-6 was a consequence of NF-kappaB inhibition. These data reveal that LMP2A modulates two key transcription factor pathways in carcinoma cells and suggest that this finding may be important in the pathogenesis of EBV-associated tumors.
Stewart
Suzanne
S
Cancer Research UK Institute for Cancer Studies and Department of Rheumatology, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Dawson
Christopher W
CW
Takada
Kenzo
K
Curnow
John
J
Moody
Cary A
CA
Sixbey
John W
JW
Young
Lawrence S
LS
D001483:Base Sequence; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000235:genetics; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism*; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000821:virology; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000502:physiology*
D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015850:Interleukin-6; D016328:NF-kappa B; D014763:Viral Matrix Proteins