The ubiquitin system is one of the central regulators of normal cellular function, and tumor viruses, including Epstein-Barr-Virus (EBV), dysregulate this machinery in the process of cell transformation. We discovered that EBV-dependent transformation of normal human B-cells induces the expression of a ubiquitin-editing enzyme named Ubiquitin C-terminal Hydrolase L1 (UCH L1). Elevated levels of this protein have been observed in many human cancers, and participation of UCH L1 in oncogenesis has become a subject for special attention. Our recent study has demonstrated that the inhibition of UCH L1 expression is required for the transformed status of EBV-transformed B-cells. Preliminary data indicate that EBV products apply distinct mechanisms to activate the uch II promoter in Type II and III of EBV latency. We plan to study the detailed mechanism of EBV-dependent up-regulation of UCH L1 in Aim I.
Aims II and III derive from unexpected discovery made while analyzing the endogenous complexes of UCH L1 in EBV-transformed B-cells that in addition to its monomer, the dimer of UCH L1 also exists in these cells. In contrast to the monomer, which has deubiquitinating activity, the dimer of UCH L1 has been shown to act as a ubiquitin ligase in vitro. We hypothesize that as a ubiquitin-editing enzyme, UCH L1 has opposite functions in cytoplasm and nuclei, and will test this hypothesis in Aims II and III. Additionally, in the context of effects on intercellular signaling in oncogenic pathways, we discovered a positive regulatory feedback between the dimer of UCH L1 and the EBV primary oncogene LMPL This is a first implication of UCH L1 dimer in regulation of tumorigenic signaling in vivo. These studies introduce an unexplored network of regulation that is likely to be relevant not only to EBV but other oncogenic pathways as well.
Ubiquitin-editing enzymes have been implicated in fundamentally important biological processes, including oncogenesis. The studies of this proposal will reveal the functional role of ubiquitin-editing enzyme UCH L1 in EBV-transformed cells and will identify a new therapeutic target in virus-associated malignancies.
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