Bypass of Senescence by the Polycomb Group Protein CBX8 Through Direct Binding to the INK4A-ARF Locus

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2007 Mar 3

PMID 17332741

Citations 98

Authors

Nikolaj Dietrich

Adrian P Bracken

Emmanuelle Trinh

Charlotte K Schjerling

Haruhiko Koseki

Juri Rappsilber

Kristian Helin

Klaus H Hansen

Affiliations

Soon will be listed here.

Abstract

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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References

Levine S, Weiss A, Erdjument-Bromage H, Shao Z, Tempst P, Kingston R . The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol Cell Biol. 2002; 22(17):6070-8. PMC: 134016. DOI: 10.1128/MCB.22.17.6070-6078.2002. View

Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V . Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002; 111(2):185-96. DOI: 10.1016/s0092-8674(02)00975-3. View

Mesnil M, Crespin S, Avanzo J, Zaidan-Dagli M . Defective gap junctional intercellular communication in the carcinogenic process. Biochim Biophys Acta. 2005; 1719(1-2):125-45. DOI: 10.1016/j.bbamem.2005.11.004. View

Vanaja D, Ballman K, Morlan B, Cheville J, Neumann R, Lieber M . PDLIM4 repression by hypermethylation as a potential biomarker for prostate cancer. Clin Cancer Res. 2006; 12(4):1128-36. DOI: 10.1158/1078-0432.CCR-05-2072. View

Bernstein E, Duncan E, Masui O, Gil J, Heard E, Allis C . Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol. 2006; 26(7):2560-9. PMC: 1430336. DOI: 10.1128/MCB.26.7.2560-2569.2006. View

Sanchez-Beato M, Sanchez E, Gonzalez-Carrero J, Morente M, Diez A, Sanchez-Verde L . Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays. Mod Pathol. 2006; 19(5):684-94. DOI: 10.1038/modpathol.3800577. View

Hake S, Allis C . Histone H3 variants and their potential role in indexing mammalian genomes: the "H3 barcode hypothesis". Proc Natl Acad Sci U S A. 2006; 103(17):6428-35. PMC: 1564199. DOI: 10.1073/pnas.0600803103. View

Bracken A, Dietrich N, Pasini D, Hansen K, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006; 20(9):1123-36. PMC: 1472472. DOI: 10.1101/gad.381706. View

Liu L, Andrews L, Tollefsbol T . Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death. Oncogene. 2006; 25(31):4370-5. PMC: 2423216. DOI: 10.1038/sj.onc.1209454. View

10.

Gil J, Peters G . Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006; 7(9):667-77. DOI: 10.1038/nrm1987. View

11.

Klose R, Kallin E, Zhang Y . JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006; 7(9):715-27. DOI: 10.1038/nrg1945. View

12.

Muller J, Hart C, Francis N, Vargas M, Sengupta A, Wild B . Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002; 111(2):197-208. DOI: 10.1016/s0092-8674(02)00976-5. View

13.

Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P . Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002; 298(5595):1039-43. DOI: 10.1126/science.1076997. View

14.

Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D . Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002; 16(22):2893-905. PMC: 187479. DOI: 10.1101/gad.1035902. View

15.

Itahana K, Zou Y, Itahana Y, Martinez J, Beausejour C, Jacobs J . Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol. 2002; 23(1):389-401. PMC: 140680. DOI: 10.1128/MCB.23.1.389-401.2003. View

16.

Dirac A, Bernards R . Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53. J Biol Chem. 2003; 278(14):11731-4. DOI: 10.1074/jbc.C300023200. View

17.

Thiebault K, Mazelin L, Pays L, Llambi F, Joly M, Scoazec J . The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment. Proc Natl Acad Sci U S A. 2003; 100(7):4173-8. PMC: 153067. DOI: 10.1073/pnas.0738063100. View

18.

Park I, Qian D, Kiel M, Becker M, Pihalja M, Weissman I . Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003; 423(6937):302-5. DOI: 10.1038/nature01587. View

19.

Seibold S, Rudroff C, Weber M, Galle J, Wanner C, Marx M . Identification of a new tumor suppressor gene located at chromosome 8p21.3-22. FASEB J. 2003; 17(9):1180-2. DOI: 10.1096/fj.02-0934fje. View

20.

Narita M, Nunez S, Heard E, Narita M, Lin A, Hearn S . Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113(6):703-16. DOI: 10.1016/s0092-8674(03)00401-x. View