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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4535-4540. Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-03-0870. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0870v1 102/13/4535    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tellam, J. Articles by Khanna, R. Search for Related Content PubMed PubMed Citation Articles by Tellam, J. Articles by Khanna, R. Related Collections Immunobiology Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity Judy Tellam, Geoff Connolly, Natasha Webb, Jaikumar Duraiswamy, and Rajiv Khanna From the Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Australia; and Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Australia. The ability of viral or mutated cellular oncogenes to initiate neoplastic events and their poor immunogenicity have considerably undermined their potential use as immunotherapeutic tools for the treatment of human cancers. Using an Epstein-Barr virus-encoded oncogene, latent membrane protein 1 (LMP1), as a model, we report a novel strategy that both deactivates cellular signaling pathways associated with the oncogenic phenotype and reverses poor immunogenicity. We show that cotranslational ubiquitination combined with N-end rule targeting of LMP1 enhanced the intracellular degradation of LMP1 and total blockade of LMP1-mediated nuclear factor-B (NF-B) and signal transducer and activator of transcription (STAT) activation in human cells. In addition, although murine cells expressing LMP1 were uniformly tumorigenic, this oncogenicity was completely abrogated by covalent linkage of LMP1 with ubiquitin, while an enhanced CD8+ T cell response to a model epitope fused to the C-terminus of LMP1 was observed following immunization with ubiquitinated LMP1. These observations suggest that proteasomal targeting of tumor-associated oncogenes could be exploited therapeutically by either gene therapy or vaccination. (Blood. 2003;102:4535-4540) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Smith, L. Beagley, and R. Khanna Acquisition of Polyfunctionality by Epstein-Barr Virus-Specific CD8+ T Cells Correlates with Increased Resistance to Galectin-1-Mediated Suppression J. Virol., June 15, 2009; 83(12): 6192 - 6198. [Abstract] [Full Text] [PDF] J. Pandya and D. M. Walling Oncogenic Activity of Epstein-Barr Virus Latent Membrane Protein 1 (LMP-1) Is Down-Regulated by Lytic LMP-1. J. Virol., August 1, 2006; 80(16): 8038 - 8046. [Abstract] [Full Text] [PDF] S. Delmas, L. Martin, M. Baron, J. A. Nelson, D. N. Streblow, and J.-L. Davignon Optimization of CD4+ T Lymphocyte Response to Human Cytomegalovirus Nuclear IE1 Protein through Modifications of Both Size and Cellular Localization J. Immunol., November 15, 2005; 175(10): 6812 - 6819. [Abstract] [Full Text] [PDF]

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