Upregulation of the cell-cycle regulator RGC-32 in epstein-barr virus-immortalized cells
Por:
Schlick S.N., Wood C.D., Gunnell A., Webb H.M., Khasnis S., Schepers A., West M.J.
Publicada:
1 ene 2011
Resumen:
Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator. © 2011 Schlick et al.
Filiaciones:
Schlick S.N.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Experimental Pneumology, Research Center Borstel, Borstel, Germany
Wood C.D.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Gunnell A.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Webb H.M.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Khasnis S.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Schepers A.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Research Unit Gene Vectors, Helmholtz Zentrum München-German Research Center for Environmental Health, München, Germany
West M.J.:
School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom
Gold
|