Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.
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.
Dietrich
Nikolaj
N
Centre for Epigenetics and Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Bracken
Adrian P
AP
Trinh
Emmanuelle
E
Schjerling
Charlotte K
CK
Koseki
Haruhiko
H
Rappsilber
Juri
J
Helin
Kristian
K
Hansen
Klaus H
KH
D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D033681:Mitochondrial Membrane Transport Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C069077:BMI1 protein, human; C570428:CBX8 protein, human; D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D033681:Mitochondrial Membrane Transport Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C570429:Cbx8 protein, mouse; D063150:Polycomb Repressive Complex 1