The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
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The p16 INK4A and p14 ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.
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Molecular mechanisms underlying CDKN2A derepression are not completely understood but have been associated with loss of polycomb group proteins and are independent of p53.
“The molecular mechanisms underlying this derepression are not completely understood but have been associated with loss of polycomb group of proteins but independent of p53 (Jacobs et al., 1999; Bracken et al., 2007).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Bracken et al., 2007
During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2, and recruitment of JMJD3 lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.
“During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2 [83], and recruitment of JMJD3 [84,85], a histone lysine demethylase that catalyzes H3K27 demethylation, lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [83]
The mechanistic details of how cells memorize excessive mitogenic stimulation involve the progressive loss of repressive Polycomb complexes.
“The mechanistic details of how this happens are starting to emerge, and seem in part to involve the progressive loss of repressive Polycomb complexes 7”
From The common biology of cancer and ageing (2007) · cites this paper as [7]
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Cites
Polycomb complexes repress developmental regulators in murine embryonic stem cells
Boyer, L. A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L. A., Lee, T. I., Levine, S. S., Wernig, M., Tajonar, A., Ray, M. K., et al. (2006) · Nature · doi:10.1038/nature04733 · Cited by 2,518 · see citing works
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · cited 1× · see citing works
“SA- -gal assays were performed as previously described (Narita et al. 2003).”
MethodControl of Developmental Regulators by Polycomb in Human Embryonic Stem Cells
Lee, T. I., Jenner, R. G., Boyer, L. A., Guenther, M. G., Levine, S. S., Kumar, R., Chevalier, B. S., Johnstone, S. E., Cole, M. F., Isono, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.043 · Cited by 2,238 · see citing works
A gene hypermethylation profile of human cancer.
Esteller, M., Corn, P. G., Baylin, S. B., & Herman, J. G. (2001) · PubMed · Cited by 2,032 · see citing works
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999) · Nature · doi:10.1038/16476 · Cited by 1,580 · see citing works
Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.
Lessard, J., & Sauvageau, G. (2003) · Nature · doi:10.1038/nature01572 · Cited by 1,452 · see citing works
Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation
Molofsky, A. V., Pardal, R., Iwashita, T., Park, I.-K., Clarke, M. F., & Morrison, S. J. (2003) · Nature · doi:10.1038/nature02060 · Cited by 1,301 · see citing works
Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitionsPreprint
Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H., & Helin, K. (2006) · Genes & Development · doi:10.1101/gad.381706 · Cited by 1,258 · see citing works
Self-citationEZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.
Bracken, A. P., Pasini, D., Capra, M., Prosperini, E., Colli, E., & Helin, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg542 · Cited by 1,196 · see citing works
Self-citationStem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106 · see citing works
The Regulation of INK4/ARF in Cancer and Aging
Kim, W. Y., & Sharpless, N. E. (2006) · Cell · doi:10.1016/j.cell.2006.10.003 · Cited by 1,009 · see citing works
Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., & Barrett, J. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13742 · Cited by 1,008 · see citing works
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003 · cited 1× · see citing works
“Recently, Ink4a and Arf have been shown to accumulate in stem cells of old mice; however, the levels of Bmi1 are unchanged (Janzen et al. 2006; Krishnamurthy et al. 2006; Molofsky et al. 2006).”
BackgroundIncreasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972 · cited 1× · see citing works
“Recently, Ink4a and Arf have been shown to accumulate in stem cells of old mice; however, the levels of Bmi1 are unchanged (Janzen et al. 2006; Krishnamurthy et al. 2006; Molofsky et al. 2006).”
BackgroundSuz12 is essential for mouse development and for EZH2 histone methyltransferase activity
Pasini, D., Bracken, A. P., Jensen, M. R., Denchi, E. L., & Helin, K. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600402 · Cited by 910 · see citing works
Self-citationThe functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3
Cao, R., & Zhang, Y. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.02.001 · Cited by 907 · see citing works
Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
Gil, J., & Peters, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1987 · Cited by 843 · see citing works
Tumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699 · cited 1× · see citing works
“Both of these proteins are encoded by the INK4A-ARF locus and are tumor suppressors that act upstream of the pRB and p53 pathways, respectively (Lowe and Sherr 2003).”
BackgroundMolofsky, A. V., He, S., Bydon, M., Morrison, S. J., & Pardal, R. (2005) · Genes & Development · doi:10.1101/gad.1299505 · Cited by 586 · see citing works
Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas
Leung, C., Lingbeek, M., Shakhova, O., Liu, J. K., Tanger, E., Saremaslani, P., van Lohuizen, M., & Marino, S. (2004) · Nature · doi:10.1038/nature02385 · Cited by 541 · see citing works
Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1
Itahana, K., Zou, Y., Itahana, Y., Martinez, J.-L., Beausejour, C., Jacobs, J. J. L., van Lohuizen, M., Band, V., Campisi, J., & Dimri, G. P. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.389-401.2003 · Cited by 438 · see citing works
The polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion
Kamminga, L. M., Bystrykh, L. V., de Boer, A., Houwer, S., Douma, J., Weersing, E., Dontje, B., & de Haan, G. (2006) · Blood · doi:10.1182/blood-2005-09-3585 · Cited by 376 · see citing works
Polycomb CBX7 has a unifying role in cellular lifespan.
Gil, J., Bernard, D., Martínez, D., & Beach, D. (2004) · Nature Cell Biology · doi:10.1038/ncb1077 · Cited by 341 · see citing works
Bruggeman, S. W. M., Valk-Lingbeek, M. E., van der Stoop, P. P. M., Jacobs, J. J. L., Kieboom, K., Tanger, E., Hulsman, D., Leung, C., Arsenijevic, Y., Marino, S., et al. (2005) · Genes & Development · doi:10.1101/gad.1299305 · Cited by 315 · see citing works
Rastelli, L., Chan, C. S., & Pirrotta, V. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05795.x · Cited by 314 · see citing works
What has senescence got to do with cancer?
Dimri, G. P. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.025 · Cited by 313 · see citing works
Suz12 binds to silenced regions of the genome in a cell-type-specific mannerPreprint
Squazzo, S. L., O’Geen, H., Komashko, V., Krig, S. R., Jin, V. X., Jang, S.-W., Margueron, R., Reinberg, D., Green, R., & Farnham, P. (2006) · Genome Research · doi:10.1101/gr.5306606 · Cited by 310 · see citing works
Histone variants, nucleosome assembly and epigenetic inheritance
Henikoff, S., Furuyama, T., & Ahmad, K. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.05.004 · Cited by 299 · see citing works
Division of labor in Polycomb group repression
Levine, S. S., King, I. F. G., & Kingston, R. E. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.07.007 · Cited by 219 · see citing works
Role of p14<sup>ARF</sup> in Replicative and Induced Senescence of Human Fibroblasts
Wei, W., Hemmer, R. M., & Sedivy, J. M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.20.6748-6757.2001 · Cited by 217 · see citing works
Histone Lysine Demethylases and Their Impact on Epigenetics
Trojer, P., & Reinberg, D. (2006) · Cell · doi:10.1016/j.cell.2006.04.003 · Cited by 212 · see citing works
Activated p53 suppresses the histone methyltransferase EZH2 gene
Tang, X., Milyavsky, M., Shats, I., Erez, N., Goldfinger, N., & Rotter, V. (2004) · Oncogene · doi:10.1038/sj.onc.1207706 · Cited by 191 · see citing works
Dietrich, N., Bracken, A. P., Trinh, E., Schjerling, C. K., Koseki, H., Rappsilber, J., Helin, K., & Hansen, K. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601632 · Cited by 187 · see citing works
Self-citationEstablishment of Polycomb silencing requires a transient interaction between PC and ESCPreprint
Poux, S., Melfi, R., & Pirrotta, V. (2001) · Genes & Development · doi:10.1101/gad.208901 · Cited by 171 · see citing works
Hernández‐Muñoz, I., Taghavi, P., Kuijl, C. P., Neefjes, J., & van Lohuizen, M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.24.11047-11058.2005 · Cited by 168 · see citing works
Oruetxebarria, I., Venturini, F., Kekarainen, T., Houweling, A., Zuijderduijn, L. M. P., Mohd-Sarip, A., Vries, R. G. J., Hoeben, R. C., & Verrijzer, C. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309333200 · Cited by 160 · see citing works
Narita, M., & Lowe, S. W. (2005) · Nature Medicine · doi:10.1038/nm0905-920 · Cited by 150 · see citing works
Polycomb Group Proteins in Cell Cycle Progression and Cancer
Pasini, D., Bracken, A. P., & Helin, K. (2004) · Cell Cycle · doi:10.4161/cc.3.4.773 · Cited by 99 · see citing works
Self-citationRaaphorst, F. M. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi111 · Cited by 89 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441 · see citing works
The Polycomb complex PRC2 and its mark in life
Margueron, R., & Reinberg, D. (2011) · Nature · doi:10.1038/nature09784 · Cited by 3,347 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
Cellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development
Agger, K., Cloos, P. A., Christensen, J. F., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A. E., & Helin, K. (2007) · Nature · doi:10.1038/nature06145 · Cited by 1,392 · see citing works
Self-citationYap, K. L., Li, S., Muñoz-Cabello, A. M., Raguz, S., Zeng, L., Mujtaba, S., Gil, J., Walsh, M. J., & Zhou, M.-M. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.03.021 · Cited by 1,391 · see citing works
Mechanisms of Polycomb gene silencing: knowns and unknowns
Simon, J. A., & Kingston, R. E. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2763 · Cited by 1,320 · see citing works
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers
Chi, P., Allis, C. D., & Wang, G. G. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2876 · Cited by 1,099 · see citing works
Shen, X., Liu, Y., Hsu, Y.-J., Fujiwara, Y., Kim, J., Mao, X., Yuan, G.-C., & Orkin, S. H. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.10.016 · Cited by 1,021 · see citing works
Epigenetic mechanisms of longevity and aging
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016) · Cell · doi:10.1016/j.cell.2016.07.050 · Cited by 956 · see citing works
Geriatric muscle stem cells switch reversible quiescence into senescence
Sousa-Victor, P., Gutarra, S., García-Prat, L., Rodriguez-Ubreva, J., Ortet, L., Ruiz-Bonilla, V., Jardí, M., Ballestar, E., González, S., Serrano, A. L., et al. (2014) · Nature · doi:10.1038/nature13013 · Cited by 1,010 · see citing works
Kotake, Y., Nakagawa, T., Kitagawa, K., Suzuki, S., Liu, N., Kitagawa, M., & Xiong, Y. (2011) · Oncogene · doi:10.1038/onc.2010.568 · Cited by 1,001 · see citing works
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988 · see citing works
Stems Cells and the Pathways to Aging and Cancer
Rossi, D. J., Jamieson, C. H. M., & Weissman, I. L. (2008) · Cell · doi:10.1016/j.cell.2008.01.036 · Cited by 895 · see citing works
Burd, C. E., Jeck, W. R., Liu, Y., Sanoff, H. K., Wang, Z., & Sharpless, N. E. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001233 · Cited by 895 · see citing works
Tumour-initiating cells: challenges and opportunities for anticancer drug discovery
Zhou, B.-B. S., Zhang, H., Damelin, M., Geles, K., Grindley, J., & Dirks, P. (2009) · Nature reviews. Drug discovery · doi:10.1038/nrd2137 · Cited by 873 · see citing works
Cellular senescence and tumor suppressor gene p16
Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012) · International Journal of Cancer · doi:10.1002/ijc.27316 · Cited by 825 · see citing works
Erasing the methyl mark: histone demethylases at the center of cellular differentiation and diseasePreprint
Cloos, P. A., Christensen, J., Agger, K., & Helin, K. (2008) · Genes & Development · doi:10.1101/gad.1652908 · Cited by 664 · see citing works
Self-citationStock, J. K., Giadrossi, S., Casanova, M., Brookes, E., Vidal, M., Koseki, H., Brockdorff, N., Fisher, A. G., & Pombo, A. (2007) · Nature Cell Biology · doi:10.1038/ncb1663 · Cited by 650 · see citing works
Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition
Yang, M., Hsu, D. S., Wang, H., Wang, H.-J., Lan, H., Yang, W., Huang, C.-H., Kao, S., Tzeng, C., Tai, S., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2099 · Cited by 631 · see citing works
Nishino, J., Kim, I., Chada, K. K., & Morrison, S. J. (2008) · Cell · doi:10.1016/j.cell.2008.09.017 · Cited by 623 · see citing works
Ezh2 Orchestrates Gene Expression for the Stepwise Differentiation of Tissue-Specific Stem Cells
Ezhkova, E., Pasolli, H. A., Parker, J. S., Stokes, N., Su, I.-H., Hannon, G. J., Tarakhovsky, A., & Fuchs, E. V. (2009) · Cell · doi:10.1016/j.cell.2008.12.043 · Cited by 599 · see citing works
Mechanisms of Stem Cell Self-Renewal
He, S., Nakada, D., & Morrison, S. J. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113248 · Cited by 607 · see citing works
Polycomb group proteins: navigators of lineage pathways led astray in cancer
Bracken, A. P., & Helin, K. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2736 · Cited by 562 · see citing works
Self-citationShah, P. P., Donahue, G., Otte, G. L., Capell, B. C., Nelson, D. M., Cao, K., Aggarwala, V., Cruickshanks, H. A., Rai, T. S., McBryan, T., et al. (2013) · Genes & Development · doi:10.1101/gad.223834.113 · Cited by 550 · see citing works
Liu, Y., Sanoff, H. K., Cho, H., Burd, C. E., Torrice, C., Ibrahim, J. G., Thomas, N. E., & Sharpless, N. E. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00489.x · Cited by 509 · see citing works
Epigenetics: The link between nature and nurture
Tammen, S. A., Friso, S., & Choi, S. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.07.018 · Cited by 498 · see citing works
Beerman, I., Bock, C., Garrison, B. S., Smith, Z. D., Gu, H., Meissner, A., & Rossi, D. J. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.01.017 · Cited by 485 · see citing works
Bmi1 regulates mitochondrial function and the DNA damage response pathway
Liu, J., Cao, L., Chen, J., Song, S., Lee, I. H., Quijano, C., Liu, H., Keyvanfar, K., Chen, H., Cao, L.-Y., et al. (2009) · Nature · doi:10.1038/nature08040 · Cited by 474 · see citing works
Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan
Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K.-D., & Bulavin, D. V. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.002 · Cited by 460 · see citing works
Trithorax group proteins: switching genes on and keeping them active
Schuettengruber, B., Martinez, A., Iovino, N., & Cavalli, G. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3230 · Cited by 454 · see citing works
Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas
Piunti, A., Hashizume, R., Morgan, M. A., Bartom, E. T., Horbinski, C. M., Marshall, S. A., Rendleman, E. J., Ma, Q., Takahashi, Y.-H., Woodfin, A. R., et al. (2017) · Nature Medicine · doi:10.1038/nm.4296 · Cited by 445 · see citing works
Pro-senescence therapy for cancer treatment
Nardella, C., Clohessy, J. G., Alimonti, A., & Pandolfi, P. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3057 · Cited by 437 · see citing works
Kashyap, V., Rezende, N. C., Scotland, K. B., Shaffer, S., Persson, J. L., Gudas, L. J., & Mongan, N. P. (2009) · Stem Cells and Development · doi:10.1089/scd.2009.0113 · Cited by 434 · see citing works
Maintaining cell identity: PRC2-mediated regulation of transcription and cancer
Comet, I. V., Riising, E. M., Leblanc, B., & Helin, K. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.83 · Cited by 428 · see citing works
Self-citationAgger, K., Cloos, P. A. C., Rudkjær, L., Williams, K., Andersen, G., Christensen, J., & Helin, K. (2009) · Genes & Development · doi:10.1101/gad.510809 · Cited by 427 · see citing works
Self-citationImplications of Genetic and Epigenetic Alterations of CDKN2A (p16 INK4a ) in Cancer
Zhao, R., Choi, B. Y., Lee, M.-H., Bode, A. M., & Dong, Z. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.04.017 · Cited by 425 · see citing works
Recruitment of Polycomb group complexes and their role in the dynamic regulation of cell fate choice
Schuettengruber, B., & Cavalli, G. (2009) · Development · doi:10.1242/dev.033902 · Cited by 424 · see citing works
Chang, C. J., Yang, J.-Y., Xia, W., Chen, C.-T., Xie, X., Chao, C.-H., Woodward, W. A., Hsu, J.-M., Hortobágyi, G. N., & Hung, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.035 · Cited by 411 · see citing works
Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers
Lee, S. T., Li, Z., Wu, Z., Aau, M., Guan, P., Karuturi, R. K. M., Liou, Y. C., & Yu, Q. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.011 · Cited by 397 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
MYC stimulates EZH2 expression by repression of its negative regulator miR-26a
Sander, S., Bullinger, L., Klapproth, K., Fiedler, K., Kestler, H. A., Barth, T. F. E., Möller, P., Stilgenbauer, S., Pollack, J. R., & Wirth, T. (2008) · Blood · doi:10.1182/blood-2008-03-147645 · Cited by 394 · see citing works
Functional Analysis of the Chromosome 9p21.3 Coronary Artery Disease Risk Locus
Jarinova, O., Stewart, A. F. R., Roberts, R., Wells, G. A., Lau, P., Naing, T., Buerki, C., McLean, B. W., Cook, R., Parker, J. S., et al. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.189522 · Cited by 384 · see citing works
The roles of Polycomb repressive complexes in mammalian development and cancer
Piunti, A., & Shilatifard, A. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00341-1 · Cited by 382 · see citing works
Bao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
Polycomb group protein-mediated repression of transcription
Morey, L., & Helin, K. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.02.009 · Cited by 380 · see citing works
Self-citationChen, H., Gu, X., Su, I.-H., Bottino, R., Contreras, J. L., Tarakhovsky, A., & Kim, S. K. (2009) · Genes & Development · doi:10.1101/gad.1742509 · Cited by 366 · see citing works
Histone demethylase JMJD3 contributes to epigenetic control of <i>INK4a/ARF</i> by oncogenic RAS
Barradas, M., Anderton, E., Acosta, J. C., Li, S., Banito, A., Rodriguez-Niedenführ, M., Maertens, G., Banck, M., Zhou, M.-M., Walsh, M. J., et al. (2009) · Genes & Development · doi:10.1101/gad.511109 · Cited by 352 · see citing works
Chromatin repressive complexes in stem cells, development, and cancer
Laugesen, A., & Helin, K. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.05.006 · Cited by 352 · see citing works
Self-citationCellular senescence and organismal aging
Jeyapalan, J. C., & Sedivy, J. M. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.04.001 · Cited by 347 · see citing works
p53-Mediated Hematopoietic Stem and Progenitor Cell Competition
Bondar, T., & Medzhitov, R. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.03.002 · Cited by 342 · see citing works
Targeted Disruption of the EZH2/EED Complex Inhibits EZH2-dependent Cancer
Kim, W., Bird, G. H., Neff, T., Guo, G., Kerényi, M., Walensky, L., & Orkin, S. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1331 · Cited by 357 · see citing works
The role of epigenetics in aging and age-related diseases
Calvanese, V., Lara, E., Kahn, A., & Fraga, M. F. (2009) · Ageing Research Reviews · doi:10.1016/j.arr.2009.03.004 · Cited by 329 · see citing works
Nonoverlapping Functions of the Polycomb Group Cbx Family of Proteins in Embryonic Stem Cells
Morey, L., Pascual, G., Cozzuto, L., Roma, G., Wutz, A., Benitah, S. A., & Croce, L. D. (2012) · Cell stem cell · doi:10.1016/j.stem.2011.12.006 · Cited by 324 · see citing works
Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence
Adams, P. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.021 · Cited by 326 · see citing works
McCord, R. P., Nazario-Toole, A., Zhang, H., Chines, P. S., Zhan, Y., Erdos, M. R., Collins, F. S., Dekker, J., & Cao, K. (2012) · Genome Research · doi:10.1101/gr.138032.112 · Cited by 326 · see citing works
Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo
Abdel-Wahab, O. I., Gao, J., Adli, M., Dey, A., Trimarchi, T., Chung, Y. R., Kuscu, C., Hricik, T., Ndiaye‐Lobry, D., LaFave, L. M., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20131141 · Cited by 322 · see citing works
Watanabe, S., Kawamoto, S., Ohtani, N., & Hara, E. (2017) · Cancer Science · doi:10.1111/cas.13184 · Cited by 321 · see citing works
He, J., Shen, L., Wan, M., Taranova, O., Wu, H., & Zhang, Y. (2013) · Nature Cell Biology · doi:10.1038/ncb2702 · Cited by 316 · see citing works
Pasini, D., Hansen, K. H., Christensen, J. F., Agger, K., Cloos, P. A., & Helin, K. (2008) · Genes & Development · doi:10.1101/gad.470008 · Cited by 315 · see citing works
Self-citationINK4 proteins, a family of mammalian CDK inhibitors with novel biological functions
Cánepa, E. T., Scassa, M. É., Ceruti, J. M., Marazita, M. C., Carcagno, A. L., Sirkin, P. F., & Ogara, M. F. (2007) · IUBMB Life · doi:10.1080/15216540701488358 · Cited by 314 · see citing works
PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylationPreprint
Hyllus, D. M., Stein, C., Schnabel, K., Schiltz, E., Imhof, A., Dou, Y., Hsieh, J. J.-D., & Bauer, U. (2007) · Genes & Development · doi:10.1101/gad.447007 · Cited by 308 · see citing works
Histone methyltransferases in cancer
Albert, M., & Helin, K. (2009) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2009.10.007 · Cited by 312 · see citing works
Self-citationFüllgrabe, J., Kavanagh, E. T., & Joseph, B. (2011) · Oncogene · doi:10.1038/onc.2011.121 · Cited by 307 · see citing works
Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance
Wilting, R. H., & Dannenberg, J. (2012) · Drug Resistance Updates · doi:10.1016/j.drup.2012.01.008 · Cited by 302 · see citing works
Cellular senescence in development, regeneration and disease
Rhinn, M., Ritschka, B., & Keyes, W. M. (2019) · Development · doi:10.1242/dev.151837 · Cited by 296 · see citing works
Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis
Wang, L., Jin, Q., Lee, J., Su, I.-H., & Ge, K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000031107 · Cited by 299 · see citing works
Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal
Zon, L. (2008) · Nature · doi:10.1038/nature07038 · Cited by 309 · see citing works
The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b
He, J., Kallin, E. M., Tsukada, Y.-I., & Zhang, Y. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1499 · Cited by 295 · see citing works
The Molecular Balancing Act of p16INK4a in Cancer and Aging
LaPak, K. M., & Burd, C. E. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0350 · Cited by 294 · see citing works
Regulation and Role of EZH2 in Cancer
Yamaguchi, H., & Hung, M. (2014) · Cancer Research and Treatment · doi:10.4143/crt.2014.46.3.209 · Cited by 291 · see citing works
Human T <sub>H</sub> 17 Cells Are Long-Lived Effector Memory Cells
Kryczek, I., Zhao, E., Liu, Y., Wang, Y., Vatan, L., Szeliga, W., Moyer, J., Klimczak, A., Lange, A., & Zou, W. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002949 · Cited by 278 · see citing works
Ito, T., Teo, Y. V., Evans, S. A., Neretti, N., & Sedivy, J. M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.002 · Cited by 265 · see citing works
SWI/SNF Mediates Polycomb Eviction and Epigenetic Reprogramming of the INK4b-ARF-INK4a Locus
Kia, S. K., Gorski, M. M., Giannakopoulos, S., & Verrijzer, C. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02019-07 · Cited by 265 · see citing works
Brien, G. L., Gambero, G., O’Connell, D. J., Jerman, E., Turner, S. A., Egan, C. M., Dunne, E. J., Jürgens, M. C., Wynne, K. J., Piao, L., et al. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2449 · Cited by 264 · see citing works
Self-citationGerminal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis
Cagánová, M., Carrisi, C., Varano, G., Mainoldi, F., Zanardi, F., Germain, P., George, L. A., Alberghini, F., Ferrarini, L., Talukder, A. K., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70626 · Cited by 256 · see citing works
Cellular senescence and Alzheimer disease: the egg and the chicken scenario
Saez-Atienzar, S., & Masliah, E. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0325-z · Cited by 257 · see citing works
INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis
Liu, Y., Sanoff, H. K., Cho, H., Burd, C. E., Torrice, C., Mohlke, K. L., Ibrahim, J. G., Thomas, N. E., & Sharpless, N. E. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005027 · Cited by 248 · see citing works
Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins
Mills, A. A. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2931 · Cited by 249 · see citing works
Kim, J., Sharma, A., Dhar, S. S., Lee, S.-H., Gu, B., Chan, C., Lin, H., & Lee, M. G. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1896 · Cited by 246 · see citing works
Stem cell regulation by polycomb repressors: postponing commitment
Pietersen, A. M., & van Lohuizen, M. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.01.004 · Cited by 248 · see citing works
EZH2-Targeted Therapies in Cancer: Hype or a Reality
Eich, M., Athar, M., Ferguson, J. E., & Varambally, S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-2147 · Cited by 246 · see citing works
PRC2 mediated H3K27 methylations in cellular identity and cancer
Conway, E., Healy, E., & Bracken, A. P. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2015.10.003 · Cited by 239 · see citing works
Self-citationRoles of the Polycomb group proteins in stem cells and cancer
Richly, H., Aloia, L., & Croce, L. D. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.84 · Cited by 241 · see citing works
Epigenetics and environment: a complex relationship.
Aguilera, O., Fernández, A., Muñoz, A., & Fraga, M. (2010) · Journal of applied physiology · doi:10.1152/japplphysiol.00068.2010 · Cited by 239 · see citing works
Klauke, K., Radulović, V., Broekhuis, M., Weersing, E., Zwart, E., Olthof, S., Ritsema, M., Bruggeman, S., Wu, X., Helin, K., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2701 · Cited by 237 · see citing works
Self-citationWitcher, M., & Emerson, B. M. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.001 · Cited by 235 · see citing works
The emerging functions of histone demethylases
Agger, K., Christensen, J. F., Cloos, P. A., & Helin, K. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2007.12.003 · Cited by 231 · see citing works
Self-citationZhang, B., Liu, X.-X., He, J.-R., Zhou, C., Guo, M., He, M., Li, M.-F., Chen, G., & Zhao, Q. (2010) · Carcinogenesis · doi:10.1093/carcin/bgq209 · Cited by 228 · see citing works
Kottakis, F., Polytarchou, C., Foltopoulou, P. F., Sanidas, I., Kampranis, S. C., & Tsichlis, P. N. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.020 · Cited by 224 · see citing works
Hidalgo, I., Herrera-Merchan, A., Ligos, J. M., Carramolino, L., Nuñez, J., Martinez, F., Dominguez, O., Torres, M., & Gonzalez, S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.08.001 · Cited by 222 · see citing works
Hallmarks of cancer—the new testament
Senga, S. S., & Grose, R. P. (2021) · Open Biology · doi:10.1098/rsob.200358 · Cited by 221 · see citing works
. Prediction, progression and outcomes of chronic kidney disease in older adults.
Anderson, S., Halter, J. B., Hazzard, W. R., Himmelfarb, J., Horne, F. M., Kaysen, G. A., Kusek, J. W., Nayfield, S. G., Schmader, K., Tian, Y., et al. (2009) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008080860 · Cited by 218 · see citing works
Polycomb Repressive Complex 2 Regulates Normal Development of the Mouse Heart
He, A., Ma, Q., Cao, J., von Gise, A., Zhou, P., Xie, H., Zhang, B., Hsing, M., Christodoulou, D. C., Cahan, P., et al. (2011) · Circulation Research · doi:10.1161/circresaha.111.252205 · Cited by 218 · see citing works
Juan, A. H., Derfoul, A., Feng, X., Ryall, J. G., Dell’Orso, S., Pasut, A., Zare, H., Simone, J. M., Rudnicki, M. A., & Sartorelli, V. (2011) · Genes & Development · doi:10.1101/gad.2027911 · Cited by 218 · see citing works
- Authors
- Bracken, A. P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Mönch, K., Minucci, S., Porse, B. T., Marine, J.-C., Hansen, K. H., & Helin, K.
- Affiliations
- University of Copenhagen (DK)
- European Institute of Oncology (IT)
- Vlaams Instituut voor Biotechnologie (BE)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-03-01
- Volume
- 21
- Issue
- 5
- Pages
- 525-530
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1820894
- OpenAlex
- W2101370480
- Cited by
- 850
- References
- 40
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 20 · 2023: 26 · 2022: 29 · 2021: 40 · 2020: 43 · 2019: 30 · 2018: 32 · 2017: 50 · 2016: 76 · 2015: 48 · 2014: 48 · 2013: 55 · 2012: 58
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Kræftens Bekæmpelse
- Sundhed og Sygdom, Det Frie Forskningsråd
- Lundbeckfonden (R9-2007-978)
- Novo Nordisk
- Novo Nordisk Fonden
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Polycomb group proteins, INK4a/ARF locus, p16INK4a, p14ARF, cellular senescence, BMI1, EZH2, polycomb repressive complex 2, H3K27me3, chromatin repression, transcriptional activation, cancer
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Line, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, Histones, Humans, Methylation, Mice, Inbred C57BL, Neoplasms, Nuclear Proteins, Histone-Lysine N-Methyltransferase, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Stem Cells, Transcription Factors, Down-Regulation, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Oligonucleotide Array Sequence Analysis, Tumor Suppressor Protein p14ARF, Chromatin Immunoprecipitation, Mice, Polycomb Repressive Complex 1, Polycomb Repressive Complex 2
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