Article

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: 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.

Download full-text

Full-text

Available from: Masanao Murakami, Aug 16, 2015
0 Followers
 · 
132 Views
  • Source
    • "Recently it was demonstrated that EBNA3C forms a complex with cyclin D1 in human cells stabilizing cyclin D1 through inhibition of its polyubiquitination (Saha et al. 2011). The EBNA3C (Planelles et al. 1996) together with Cdk6–cyclin D1 complex also efficiently nullifies the inhibitory effect of pRB on cell growth. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Viruses depend on host cell resources for replication and access to those resources may be limited to a particular phase of the cell cycle. Thus manipulation of cell cycle is a commonly employed strategy of viruses for achieving a favorable cellular environment. For example, viruses capable of infecting nondividing cells induce S phase in order to activate the host DNA replication machinery and provide the nucleotide triphosphates necessary for viral DNA replication (Flemington in J Virol 75:4475-4481, 2001; Sullivan and Pipas in Microbiol Mol Biol Rev 66:179-202, 2002). Viruses have developed several strategies to subvert the cell cycle by association with cyclin and cyclin-dependent kinase complexes and molecules that regulate their activity. Viruses tend to act on cellular proteins involved in a network of interactions in a way that minimal protein-protein interactions lead to a major effect. The complex and interactive nature of intracellular signaling pathways controlling cell division affords many opportunities for virus manipulation strategies. Taking the maxim "Set a thief to catch a thief" as a counter strategy, however, provides us with the very same virus evasion strategies as "ready-made tools" for the development of novel antivirus therapeutics. The most obvious are attenuated virus vaccines with critical evasion genes deleted. Similarly, vaccines against viruses causing cancer are now being successfully developed. Finally, as viruses have been playing chess with our cell biology and immune responses for millions of years, the study of their evasion strategies will also undoubtedly reveal new control mechanisms and their corresponding cellular intracellular signaling pathways.
    Protoplasma 10/2011; 249(3):519-28. DOI:10.1007/s00709-011-0327-9 · 3.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes a life-long asymptomatic infection in immunocompetent hosts. It is also found to be frequently associated with a broad spectrum of B-cell lymphomas predominantly seen in immunodeficient patients. Despite many resemblances, these EBV-linked lymphoproliferative disorders display heterogeneity at the clinical and the molecular level. Moreover, EBV-associated lymphoproliferative diseases differ in their differential expression patterns of the EBV-encoded latent antigens, which are directly related to their interactions with the host. EBV-driven primary B-cell immortalization is linked to the cooperative functions of these latent proteins, which are critical for perturbing many important cell-signaling pathways maintaining B-cell proliferation. Additionally, it is used as a surrogate model to explore the underlying mechanisms involved in the development of B-cell neoplasms. Recent discoveries have revealed that a number of sophisticated mechanisms are exploited by EBV during cancer progression. This finding will be instrumental in the design of novel approaches for therapeutic interventions against EBV-associated B-cell lymphomas. This review limits the discussion to the biology and pathogenesis of EBV-associated B-cell lymphomas and the related clinical implications.
    Clinical Cancer Research 03/2011; 17(10):3056-63. DOI:10.1158/1078-0432.CCR-10-2578 · 8.19 Impact Factor
  • Nature Reviews Microbiology 04/2011; 9(4):226. · 23.32 Impact Factor
Show more