Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.

TY - JOUR

T1 - Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.

AU - Dietrich, Nikolaj

AU - Bracken, Adrian P

AU - Trinh, Emmanuelle

AU - Schjerling, Charlotte K

AU - Koseki, Haruhiko

AU - Rappsilber, Juri

AU - Helin, Kristian

AU - Hansen, Klaus

N1 - Keywords: Animals; Cell Aging; Cell Proliferation; Chromatin; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase Inhibitor p16; Fibroblasts; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Humans; Mice; Microscopy, Fluorescence; Nuclear Proteins; Proto-Oncogene Proteins; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1038/sj.emboj.7601632

DO - 10.1038/sj.emboj.7601632

M3 - Journal article

C2 - 17332741

SN - 0261-4189

VL - 26

SP - 1637

EP - 1648

JO - EMBO Journal

JF - EMBO Journal

IS - 6

ER -