Nancy Raab-Traub
Microbiology & Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill,NC 27599-7295
(Tel: 919-966-1701 Fax: 919-966-9673 E-mail: nrt@med.unc.edu)
The Epstein-Barr virus (EBV) contributes to the development of several human cancers that develop in lymphoid and epithelial cell including post-transplant lymphomas and nasopharyngeal carcinoma (NPC). The viral genome contains variable numbers of direct repeats yet is clonal in these malignancies. This suggests that the malignancies are also clonal and that EBV infection preceded clonal expansion. Viral expression in most of the malignancies includes the EBV latent membrane proteins 1 and 2 (LMP1 and LMP2), the EBV nuclear antigen 1 (EBNA1), the EBER transcripts, and a family of RNAS encoded by the BamHI A restriction enzyme EBV fragment. The LMP1 protein is expressed in all cells in examples of severe dysplasia and carcinoma in situ of the nasopharynx. LMP1 induces expression of the epithelial cell growth factor receptor (EGFR) and blocks p53-mediated apoptosis. These properties are reflected in NPC which has high levels of EGFR expression and lacks mutations in p53. A second gene expressed in NPC is LMP2. LMP2 has profound effects on epithelial cell growth where it induces proliferation and inhibits differentiation through P13-kinase and Akt activation. Activated Akt is also detected in NPC. Putative proteins encoded by the BamHI A transcripts are also likely to affect epithelial cell growth. One open reading frame identified in the RNAS is RK-BARFO. RK-BARFO interacts with the Notch ligand binding domain, as determined by yeast two-hybrid screening, co-immunoprecipitation, and confocal microscopy. This interaction induces Notch degradation. Expression of RK-BARFO in the EBNA2 negative HR1 cell line induces expression of LMP1 and this induction is dependent upon the Notch interaction domain. These data indicate that RK-BARFO affects LMP1 expression and may also alter cellular signaling pathways. The consistent expression of multiple viral proteins in EBV associated malignancies provides new opportunities for anti-viral therapies targeted to viral:cell protein interactions and virally activated signaling pathways.
References:
(1) Raab-Traub, N., and Flynn K. (1986). The Structure of the Termini of the Epstein-Barr Virus as a Marker of Clonal Cellular Proliferation. Cell 47: 883-889.
(2) Effert, P., Abdel-Hamid, M., McCoy, R., Flynn, K., Busson, P., Zhang, Q., Tursz, T., Liu, E., and Raab-Traub, N. (1992). Alterations of the p53 gene in Nasopharyngeal Carcinoma. J. Virol. 66:3768-3775.
(3) Sadler, R.H., and Raab-Traub, N. (1995). Structural Analyses of the Epstein-Barr virus BamHI A Transcripts. J.Virol. 69: 1132-1141.
(4) Miller, W.E., Earp, H.S., and Raab-Traub, N. (1995). The Epstein-Barr Virus Latent Membrane Protein I Induces Expression of the Epidermal Growth Factor Receptor. J.Virol. 69(7):4390-4398.
(5) Fries, K., Miller, W.E., and Raab-Traub N. (1996). Epstein-Barr Virus Latent Membrane Protein I blocks p53-mediated Apoptosis through the Induction of the A20 gene. J.Virol. 70:8653-8659.
(6) Scholle, F. and Raab-Traub, N. (2000). Epstein Barr Virus LMP2A Transforms Epithelial Cells, Inhibits Cell Differentiation, and Activates Akt. J. Virol. 74: 10681-10689.
(7) Kusano, S., and Raab-Traub, N. (2001). An Epstein-Barr Virus Protein Interacts with Notch in Epithelial Cells. J.Virol. 75: 384-395.
Nancy Raab-Traub PhD 1969 BS University of Michigan, USA
1980 PhD University of Chicago, USA
1980-83 Post-doctoral fellow, University of North Carolina
1985 Assistant Professor, University of North Carolina
1990 Associate Professor, University of North Carolina
1993 Full Professor, University of North Carolina
Speciality and Special Interest:
Epstein-Barr Virus, viral oncogenesis, nasopharyngeal carcinoma, signal transduction, tumor suppressor genes, apoptosis