Epstein-Barr Virus Nuclear Antigen 3C Facilitates G1-S Transition by Stabilizing and Enhancing the Function of Cyclin D1

University of North Carolina at Chapel Hill, United States of America
PLoS Pathogens (Impact Factor: 7.56). 02/2011; 7(2):e1001275. DOI: 10.1371/journal.ppat.1001275
Source: PubMed


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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Available from: Masanao Murakami, Oct 08, 2015
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    • "Cyclin A is involved in meiotic progression and has markedly lower expression in cells arrested in the G1 phase33,34,35. Cyclin D1 is a key regulator of the G1 to S phase progression and is aberrantly expressed in numerous human cancers36. The inhibition of cyclin D1 function results in G1 phase arrest, whereas the regulation of G2/M phases primarily depends on cyclin B1 function37. "
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    • "Increased CaM causes differences in the organization of microfilaments, intermediate filaments, & microtubules; these changes are accompanied by differences in the cell-cycle dependent expression of some mRNAs [49]. For efficient viral replication, viruses such as EBV, HIV-1 induce cell cycle transition from G1 to S phase [50], [51]. So it is possible that during early RV infection (3 hpi) cell cycle progresses from G1 to S phase. "
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    • "Viral genes can induce changes in the cell cycle of the host cell during the immortalization of B lymphocytes by EBV [8]. EBV latent proteins can up-regulate cyclin D1 expression in host cell, initiate the cell cycle and promote the G1-S phase transition through several signaling pathways [9,10]. EBV can also induce the up-regulation of CDK2 and CDK1 in the host cell [11]. "
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