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| Subject Categories: Cell Cycle | Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 1637–1648, doi:10.1038/sj.emboj.7601632 Published online 1 March 2007 |
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| Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus |
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| Nikolaj Dietrich1, Adrian P Bracken1, Emmanuelle Trinh1, Charlotte K Schjerling2, Haruhiko Koseki3, Juri Rappsilber4, Kristian Helin1 and Klaus H Hansen1 |
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1 Centre for Epigenetics and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark 2 Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark 3 RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Japan 4 Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh, Scotland To whom correspondence should be addressed Kristian Helin, Centre for Epigenetics, Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark. Tel.: +45 3532 5666; Fax: +45 3532 5669; E-mail: kristian.helin@bric.dk Klaus H Hansen, Tel.: +45 3532 5664; Fax: +45 3532 5669; E-mail: klaus.hansen@bric.dk Received 1 September 2006; Accepted 6 February 2007; Published online 1 March 2007. |
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| Abstract |
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| The Polycomb group (PcG) proteins are essential for embryogenesis, and their expression is often found deregulated in human cancer. The PcGs form two major protein complexes, called polycomb repressive complexes 1 and 2 (PRC1 and PRC2) whose function is to maintain transcriptional repression. Here, we demonstrate that the chromodomain-containing protein, CBX8, which is part of one of the PRC1 complexes, regulates proliferation of diploid human and mouse fibroblasts through direct binding to the INK4A-ARF locus. Furthermore, we demonstrate that CBX8 is limiting for the regulation of INK4A-ARF, and that ectopic expression of CBX8 leads to repression of the Ink4a-Arf locus and bypass of senescence, leading to cellular immortalization. Gene expression and location analysis demonstrate that besides the INK4A-ARF locus, CBX8 also regulates a number of other genes important for cell growth and survival. On the basis of these results, we conclude that CBX8 is an essential component of one of the PRC1 complexes, which directly regulate the expression of numerous target genes, including the INK4A-ARF locus, involved in cell-fate decisions. |
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| Keywords: ARF, CBX8, INK4A, Polycomb, senescence |
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