Abstract
In multicellular organisms p53 maintains genomic integrity through activation of DNA repair, and apoptosis. EBNA3C can down regulate p53 transcriptional activity. Aurora kinase (AK) B phosphorylates p53, which leads to degradation of p53. Aberrant expression of AK-B is a hallmark of numerous human cancers. Therefore changes in the activities of p53 due to AK-B and EBNA3C expression is important for understanding EBV-mediated cell transformation. Here we show that the activities of p53 and its homolog p73 are dysregulated in EBV infected primary cells which can contribute to increased cell transformation. Further, we showed that the ETS-1 binding site is crucial for EBNA3C-mediated up-regulation of AK-B transcription. Further, we determined the Ser 215 residue of p53 is critical for functional regulation by AK-B and EBNA3C and that the kinase domain of AK-B which includes amino acid residues 106, 111 and 205 was important for p53 regulation. AK-B with a mutation at residue 207 was functionally similar to wild type AK-B in terms of its kinase activities and knockdown of AK-B led to enhanced p73 expression independent of p53. This study explores an additional mechanism by which p53 is regulated by AK-B and EBNA3C contributing to EBV-induced B-cell transformation.
Highlights
Epstein-Barr virus (EBV) is a γ-herpesvirus that establishes a lifetime infection in most of the adult human population [1]
This study explores an additional mechanism by which p53 is regulated by Aurora kinase (AK)-B and EBNA3C contributing to EBV-induced B-cell transformation
We investigated the important domains of p53 which are regulated by AK-B and EBNA3C to contribute to EBVinduced oncogenesis
Summary
Epstein-Barr virus (EBV) is a γ-herpesvirus that establishes a lifetime infection in most of the adult human population [1]. A growing number of studies have suggested an essential role for EBNA3C in viral associatedoncogenesis, through direct interactions with regulator proteins responsible for maintaining cell-cycle checkpoints. P53 is activated in response to cellular stress, normally in the form of DNA or ribosomal damage, and can trigger different pathways to cell arrest or apoptosis [23]. Extensive research has focused on the separate roles of p53 and AK-B in regulating numerous cellular activities While this approach can provide an in-depth understanding of a single protein, it glosses over the numerous pathways that are linked to these two critical proteins and the regulatory activities that result from their interaction. An essential EBV latent protein like EBNA3C may have the potential to disrupt this equilibrium, and so lead to aberrant cell cycle and oncogenic activities which drives transformation of infected cells
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