Epstein-Barr virus nuclear antigen 3C facilitates G1-S transition by stabilizing and enhancing the function of cyclin D1.

Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, United States of America.
PLoS Pathogens (Impact Factor: 8.06). 02/2011; 7(2):e1001275. DOI: 10.1371/journal.ppat.1001275
Source: PubMed

ABSTRACT EBNA3C, one of the Epstein-Barr virus (EBV)-encoded latent antigens, is essential for primary B-cell transformation. Cyclin D1, a key regulator of G1 to S phase progression, is tightly associated and aberrantly expressed in numerous human cancers. Previously, EBNA3C was shown to bind to Cyclin D1 in vitro along with Cyclin A and Cyclin E. In the present study, we provide evidence which demonstrates that EBNA3C forms a complex with Cyclin D1 in human cells. Detailed mapping experiments show that a small N-terminal region which lies between amino acids 130-160 of EBNA3C binds to two different sites of Cyclin D1- the N-terminal pRb binding domain (residues 1-50), and C-terminal domain (residues 171-240), known to regulate Cyclin D1 stability. Cyclin D1 is short-lived and ubiquitin-mediated proteasomal degradation has been targeted as a means of therapeutic intervention. Here, we show that EBNA3C stabilizes Cyclin D1 through inhibition of its poly-ubiquitination, and also increases its nuclear localization by blocking GSK3β activity. We further show that EBNA3C enhances the kinase activity of Cyclin D1/CDK6 which enables subsequent ubiquitination and degradation of pRb. EBNA3C together with Cyclin D1-CDK6 complex also efficiently nullifies the inhibitory effect of pRb on cell growth. Moreover, an sh-RNA based strategy for knock-down of both cyclin D1 and EBNA3C genes in EBV transformed lymphoblastoid cell lines (LCLs) shows a significant reduction in cell-growth. Based on these results, we propose that EBNA3C can stabilize as well as enhance the functional activity of Cyclin D1 thereby facilitating the G1-S transition in EBV transformed lymphoblastoid cell lines.

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    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.
    Oncotarget 02/2015; · 6.63 Impact Factor
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    Molecular Oncology 09/2014; 10.1016/j.molonc.2014.09.006. DOI:10.1016/j.molonc.2014.09.006 · 5.94 Impact Factor
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    ABSTRACT: Ubiquitination is one of the most important post-translational modifications of proteins with a profound effect on their intracellular stability and activity. Deubiquitinases (DUBs), on the other hand, act by removing the ubiquitin moiety from proteins and thereby reverse their stability and/or activity. Besides, DUBs play a major role in maintenance of free ubiquitin pool, histone modification, vesicular trafficking and receptor recycling. The revelation of DUB interactome by Sowa et al., [1] highlighted their importance of DUBs in key cellular pathways. While the role of E3 ubiquitin ligases in the virus biology is well documented, the involvement of DUBs in viral life cycle is still being probed. Recent findings suggest DUBs could play a central role in invasion and pathogenesis of oncogenic viruses. Viral oncoproteins such as E6 and E7 of human papilloma virus and Tax of human T-cell leukemia virus type 1 are now known to targetcellular DUBs such as cyclindromatosis tumor suppressor, ubiquitin-specific proteases 7, 11, 15 and 20, A-20 and signal-transducing adaptor molecule binding protein-like-1 in order to improve their intracellular stability and/or subjugate cellular signaling pathways. The viral oncoprotein-DUB interactions create an ambience leading to unbridled proliferation of virus-infected cells and drive cell transformation.Interestingly, some viruses like herpes simplex virus-1, Epstein-Barr virus, human cytomegalovirus and Kaposi’s Sarcoma-associated herpes virus also encode their own DUBs such as UL36, UL48, BPLF1 and ORF64to support viral invasion, replication, and persistence and even subvert host immune responses. Efforts are also underway to find specific inhibitors that can abrogate the interaction between cellular DUB andviral oncoproteins or inhibit viral DUBs as this might result in the development of next generation cancer chemotherapeutic agents. This review showcases the relevance of the viral DUBs and the cellular DUBs with interacting viral partners in virus-triggered cancer development.
    01/2013; DOI:10.7243/2052-6202-1-5

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