Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity

Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Queensland, Australia
Blood (Impact Factor: 10.43). 01/2004; 102(13):4535-40. DOI: 10.1182/blood-2003-03-0870
Source: PubMed

ABSTRACT 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-kappaB (NF-kappaB) 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.

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Available from: Jaikumar Duraiswamy, Aug 25, 2015
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    • "This is associated with decreased activation of NFjB and STAT in human cells and a subsequent increase in sensitivity to apoptosis of ubiquitinated-LMP1-expressing fibroblasts. There was abrogation of the oncogenic phenotype in nude mice, whilst in BALB/c mice an enhanced CD8 + T cell response to a model epitope fused to the C-terminus of LMP1 was observed following immunization with ubiquitinated LMP1 (Tellam et al, 2003). It is important to stress that a model epitope was used in this study to assess the immunogenicity of ubiquitinated LMP1, and formal validation of this approach would require further studies based on an LMP1- derived epitope. "
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