Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells

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). Th...

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Main Authors:	Schlick, Sandra N., Wood, C. David, Gunnell, Andrea, Webb, Helen M., Khasnis, Sarika, Schepers, Aloys, West, Michelle J.
Format:	Online
Language:	English
Published:	Public Library of Science 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232240/

id	pubmed-3232240
recordtype	oai_dc
spelling	pubmed-32322402011-12-09 Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells Schlick, Sandra N. Wood, C. David Gunnell, Andrea Webb, Helen M. Khasnis, Sarika Schepers, Aloys West, Michelle J. Research Article 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. Public Library of Science 2011-12-06 /pmc/articles/PMC3232240/ /pubmed/22163048 http://dx.doi.org/10.1371/journal.pone.0028638 Text en Schlick et al. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Schlick, Sandra N. Wood, C. David Gunnell, Andrea Webb, Helen M. Khasnis, Sarika Schepers, Aloys West, Michelle J.
spellingShingle	Schlick, Sandra N. Wood, C. David Gunnell, Andrea Webb, Helen M. Khasnis, Sarika Schepers, Aloys West, Michelle J. Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells
author_facet	Schlick, Sandra N. Wood, C. David Gunnell, Andrea Webb, Helen M. Khasnis, Sarika Schepers, Aloys West, Michelle J.
author_sort	Schlick, Sandra N.
title	Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells
title_short	Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells
title_full	Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells
title_fullStr	Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells
title_full_unstemmed	Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells
title_sort	upregulation of the cell-cycle regulator rgc-32 in epstein-barr virus-immortalized cells
description	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.
publisher	Public Library of Science
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232240/
_version_	1611492507717206016

Upregulation of the Cell-Cycle Regulator RGC-32 in Epstein-Barr Virus-Immortalized Cells

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