Nancy Raab-Traub, Ph.D.

nrt@med.unc.edu 32-004 Lineberger Comprehensive Cancer Center Campus Box 7295 Chapel Hill, NC 27599-7295 919.966.1701

Research

Our laboratory investigates the role of the Epstein-Barr virus in the etiology of human disease. EBV is a ubiquitous infectious agent, which is associated with specific malignancies including Burkitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma (NPC), which develop with high incidence in endemic areas. EBV is etiologic for post-transplant lymphoma and also causes the AIDS-associated disease, hairy leukoplakia (HLP).

We have identified the genes that are expressed in NPC by cloning and sequencing cDNAs directly from tumor tissue. These studies have identified three viral genes, which are consistently expressed and have identified a new family of transcripts that are expressed at particularly high levels in NPC tissue.

These new mRNAs are intricately spliced and contain several new open reading frames which could potentially code for protein. We have shown one of these open reading frames does encode a protein that is expressed at high levels in EBV associated cancers. Current studies are investigating the potential functions of this gene using the two hybrid analysis in yeast cells and by determining its intracellular location with confocal microscopy.

Two of the proteins expressed in EBV associated cancers are membrane proteins, LMP1 and LMP2. LMP1 is considered by the EBV oncogene as it can transform rodent fibroblasts. LMP1 interacts with signaling molecules called TRAFs. In epithelial cells and fibroblasts, this interaction induces the expression of the epidermal growth factor. This induction is likely to be an important component in nasopharyngeal carcinoma.

We have successfully established three lineages of transgenic mice that express the LMP1 protein in B cells. These mice have increased development of lymphoma. In the lymphoma tissue, LMP1 is consistently expressed and the cellular oncogenes, c-myc, bcl2, and A20 are detected at high levels. This suggests that activation of expression of these cellular genes is an important component of LMP1 mediated lymphomagenesis. A single lineage has also been established for LMP2, which is expressed under the control of the immunoglobulin heavy chain enhancer and promoter. This lineage is as yet completely uncharacterized.
Future projects will continue to investigate the molecular properties of the viral proteins that are expressed in cancers associated with EBV with particular focus on the new family of mRNAs and the novel open reading frames they contain. The proteins will be expressed with epitope tags in cell lines to determine their cellular localization and molecular interactions. In addition, transgenic mice that express the proteins in particular tissues can be established and future lineages that are transgenic for more than one EBV protein can be produced through interbreeding of the existing transgenic lineages.

Publications

Marquitz AR, Mathur A, Nam CS, Raab-Traub N (2011). The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim. Virology. 412(2):392-400.

Kung CP, Meckes DG Jr, Raab-Traub N (2011). Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta. J Virol. 85(9):4399-408.

Meckes DG Jr, Shair KH, Marquitz AR, Kung CP, Edwards RH, Raab-Traub N (2010). Human tumor virus utilizes exosomes for intercellular communication.
Proc Natl Acad Sci U S A. 107(47):20370-5.

Kung CP, Raab-Traub N (2010). Epstein-Barr virus latent membrane protein 1 modulates distinctive NF- kappaB pathways through C-terminus-activating region 1 to regulate epidermal growth factor receptor expression. J Virol. 84(13):6605-14.

Everly DN Jr, Mainou BA, Raab-Traub N (2009). Transcriptional downregulation of p27KIP1 through regulation of E2F function during LMP1-mediated transformation. J Virol. 83(24):12671-9.

Shair KH, Schnegg CI, Raab-Traub N (2009). Epstein-Barr virus latent membrane protein-1 effects on junctional plakoglobin and induction of a cadherin switch. Cancer Res. 69(14):5734-42.

Shair KH, Schnegg CI, Raab-Traub N (2008). EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration. Cancer Res. 68(17):6997-7005.

Edwards RH, Marquitz AR, Raab-Traub N (2008). Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing. J Virol. 82(18):9094-106.

Siler CA, Raab-Traub N (2008). Rhesus lymphocryptovirus latent membrane protein 2A activates beta-catenin signaling and inhibits differentiation in epithelial cells. Virology. 377(2):273-9.

Everly DN Jr, Mainou BA, Raab-Traub N (2008). The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation. Virology. 376(2):258-69.

Kung CP, Raab-Traub N (2008). Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor through effects on Bcl-3 and STAT3. J Virol. 82(11):5486-93.

Shair KH, Bendt KM, Edwards RH, Bedford EC, Nielsen JN, Raab-Traub N (2007). EBV latent membrane protein 1 activates Akt, NFkappaB, and Stat3 in B cell lymphomas. PLoS Pathog. 3(11):e166.

Thornburg NJ, Raab-Traub N (2007). Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal-activating region 1 is mediated by NF-kappaB p50 homodimer/Bcl-3 complexes. J Virol. 81(23):12954-61.

Mainou BA, Everly DN Jr, Raab-Traub N (2007). Unique signaling properties of CTAR1 in LMP1-mediated transformation. J Virol. 81(18):9680-92.

Mainou BA, Raab-Traub N (2006). LMP1 strain variants: biological and molecular properties. J Virol. 80(13):6458-68.

Mainou BA, Everly DN Jr, Raab-Traub N (2005). Epstein-Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K. Oncogene. 24(46):6917-24.

Morrison JA, Raab-Traub N (2005). Roles of the ITAM and PY motifs of Epstein-Barr virus latent membrane protein 2A in the inhibition of epithelial cell differentiation and activation of {beta}-catenin signaling. J Virol. 79(4):2375-82.

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Affiliations

Department of Microbiology and Immunology
Lineberger Comprehensive Cancer Center