Abstract
Ki-67 protein has been widely used as a proliferation marker for human tumor cells for decades. In recent studies, multiple molecular functions of this large protein have become better understood. Ki-67 has roles in both interphase and mitotic cells, and its cellular distribution dramatically changes during cell cycle progression. These localizations correlate with distinct functions. For example, during interphase, Ki-67 is required for normal cellular distribution of heterochromatin antigens and for the nucleolar association of heterochromatin. During mitosis, Ki-67 is essential for formation of the perichromosomal layer (PCL), a ribonucleoprotein sheath coating the condensed chromosomes. In this structure, Ki-67 acts to prevent aggregation of mitotic chromosomes. Here, we present an overview of functional roles of Ki-67 across the cell cycle and also describe recent experiments that clarify its role in regulating cell cycle progression in human cells.
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Banani SF, Rice AM, Peeples WB, Lin Y, Jain S, Parker R, Rosen MK (2016) Composition control of phase-separated cellular bodies. Cell 166(3):651–663. https://doi.org/10.1016/j.cell.2016.06.010
Barr ML, Bertram EG (1949) A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163(4148):676–677. https://doi.org/10.1038/163676a0
Booth DG, Earnshaw WC (2017) Ki-67 and the chromosome periphery compartment in mitosis. Trends Cell Biol S0962-8924(12):30136–30138. https://doi.org/10.1016/j.tcb.2017.08.001
Booth DG, Takagi M, Sanchez-Pulido L, Petfalski E, Vargiu G, Samejima K, Imamoto N, Ponting CP, Tollervey D, Earnshaw WC, Vagnarelli P (2014) Ki-67 is a PP1-interacting protein that organises the mitotic chromosome periphery. elife 3. https://doi.org/10.7554/eLife.01641
Booth DG, Beckett AJ, Molina O, Samejima I, Masumoto H, Kouprina N, Larionov V, Prior IA, Earnshaw WC (2016) 3D-CLEM reveals that a major portion of mitotic chromosomes is not chromatin. Mol Cell 64(4):790–802. https://doi.org/10.1016/j.molcel.2016.10.009
Bostick M, Kyong KJ, Esteve P-O et al (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317(80):1760–1764. https://doi.org/10.1126/science.1147939
Bridger JM, Kill IR, Lichter P (1998) Association of pKi-67 with satellite DNA of the human genome in early G 1 cells. Chromosom Res 6(1):13–24. https://doi.org/10.1023/A:1009210206855
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR (1991) The E2F transcription factor is a cellular target for the RB protein. Cell 65(6):1053–1061. https://doi.org/10.1016/0092-8674(91)90557-F
Cheutin T, O'Donohue MF, Beorchia A, Klein C, Kaplan H, Ploton D (2003) Three-dimensional organization of pKi-67: a comparative fluorescence and electron tomography study using FluoroNanogold. J Histochem Cytochem 51(11):1411–1423
Chierico L, Rizzello L, Guan L, Joseph AS, Lewis A, Battaglia G (2017) The role of the two splice variants and extranuclear pathway on Ki-67 regulation in non-cancer and cancer cells. PLoS One 12(2):e0171815. https://doi.org/10.1371/journal.pone.0171815
Cidado J, Wong HY, Rosen DM et al (2016) Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget 7:6281–6293. https://doi.org/10.18632/oncotarget.7057
Cuylen S, Blaukopf C, Politi AZ, Müller-Reichert T, Neumann B, Poser I, Ellenberg J, Hyman AA, Gerlich DW (2016) Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature 535(7611):308–312. https://doi.org/10.1038/nature18610
de Castro IJ, Budzak J, Di Giacinto ML, Ligammari L, Gokhan E, Spanos C, Moralli D, Richardson C, de las Heras JI, Salatino S, Schirmer EC, Ullman KS, Bickmore WA, Green C, Rappsilber J, Lamble S, Goldberg MW, Vinciotti V, Vagnarelli P (2017) Repo-man/PP1 regulates heterochromatin formation in interphase. Nat Commun 8:14048. https://doi.org/10.1038/ncomms14048
Dillinger S, Straub T, Nemeth A (2017) Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation. PLoS One 12(6):e0178821. https://doi.org/10.1371/journal.pone.0178821
Dowsett M, Nielsen TO, A’Hern R et al (2011) Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group. J Natl Cancer Inst 103(22):1656–1664. https://doi.org/10.1093/jnci/djr393
Durocher D, Jackson SP (2002) The FHA domain. FEBS Lett 513(1):58–66. https://doi.org/10.1016/S0014-5793(01)03294-X
Durocher D, Henckel J, Fersht AR, Jackson SP (1999) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4(3):387–394. https://doi.org/10.1016/s1097-2765(00)80340-8
Eissenberg JC, Elgin S (2014) HP1a: a structural chromsomal protein regulating transcription. Trends Genet 30(3):103–110. https://doi.org/10.1016/j.tig.2014.01.002
El-Deiry WS, Tokino T, Velculescu VE et al (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75(4):817–825. https://doi.org/10.1016/0092-8674(93)90500-P
Endl E, Gerdes J (2000) Posttranslational modifications of the Ki-67 protein coincide with two major checkpoints during mitosis. J Cell Physiol 182(3):371–380. https://doi.org/10.1002/(SICI)1097-4652(200003)182:3<371::AID-JCP8>3.0.CO;2-J
Fedoriw AM, Calabrese JM, Mu W et al (2012) Differentiation-driven nucleolar association of the mouse imprinted Kcnq1 locus. G3 2:1521–1528. https://doi.org/10.1534/g3.112.004226
Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L, Richardson TM, Kriwacki RW, Pappu RV, Brangwynne CP (2016) Coexisting liquid phases underlie nucleolar subcompartments. Cell 165(7):1686–1697. https://doi.org/10.1016/j.cell.2016.04.047
Fischer M, Grossmann P, Padi M, DeCaprio JA (2016) Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks. Nucleic Acids Res 44(13):6070–6086. https://doi.org/10.1093/nar/gkw523
Fischle W, Tseng BS, Dormann HL, Ueberheide BM, Garcia BA, Shabanowitz J, Hunt DF, Funabiki H, Allis CD (2005) Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438(7071):1116–1122. https://doi.org/10.1038/nature04219
Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3(11):1427–1438
Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31(9):2305–2312. https://doi.org/10.1093/nar/gkg332
Garrigues JM, Sidoli S, Garcia BA, Strome S (2015) Defining heterochromatin in C. elegans through genome-wide analysis of the heterochromatin protein 1 homolog HPL-2. Genome Res 25(1):76–88. https://doi.org/10.1101/gr.180489.114
Gehani SS, Agrawal-Singh S, Dietrich N, Christophersen NS, Helin K, Hansen K (2010) Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Mol Cell 39(6):886–900. https://doi.org/10.1016/j.molcel.2010.08.020
Gerdes J, Schwab U, Lemke H, Stein H (1983) Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 31(1):13–20. https://doi.org/10.1002/ijc.2910310104
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133(4):1710–1715
Gerdes J, Stein H, Pileri S, Rivano MT, Gobbi M, Ralfkiaer E, Nielsen KM, Pallesen G, Bartels H, Palestro G, Delsol G (1987) Prognostic relevance of tumour-cell growth fraction in malignant non- Hodgkin’s lymphomas. Lancet 2(8556):448–449. https://doi.org/10.1016/S0140-6736(87)90977-9
Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, Stahmer I, Kloth S, Brandt E, Flad HD (1991) Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol 138(4):867–873
Hacisuleyman E, Goff LA, Trapnell C, Williams A, Henao-Mejia J, Sun L, McClanahan P, Hendrickson DG, Sauvageau M, Kelley DR, Morse M, Engreitz J, Lander ES, Guttman M, Lodish HF, Flavell R, Raj A, Rinn JL (2014) Topological organization of multichromosomal regions by the long intergenic noncoding RNA firre. Nat Struct Mol Biol 21(2):198–206. https://doi.org/10.1038/nsmb.2764
Hayashi Y, Kato K, Kimura K (2017) The hierarchical structure of the perichromosomal layer comprises Ki67, ribosomal RNAs, and nucleolar proteins. Biochem Biophys Res Commun 493(2):1043–1049. https://doi.org/10.1016/j.bbrc.2017.09.092
Hernandez AR, Klein AM, Kirschner MW (2012) Kinetic responses of beta-catenin specify the sites of wnt control. Science 338(80):1337–1340. https://doi.org/10.1126/science.1228734
Hiragami-Hamada K, Soeroes S, Nikolov M, Wilkins B, Kreuz S, Chen C, de la Rosa-Velázquez IA, Zenn HM, Kost N, Pohl W, Chernev A, Schwarzer D, Jenuwein T, Lorincz M, Zimmermann B, Walla PJ, Neumann H, Baubec T, Urlaub H, Fischle W (2016) Dynamic and flexible H3K9me3 bridging via HP1β dimerization establishes a plastic state of condensed chromatin. Nat Commun 7:11310. https://doi.org/10.1038/ncomms11310
Ishida S, Huang E, Zuzan H, Spang R, Leone G, West M, Nevins JR (2001) Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol 21(14):4684–4699. https://doi.org/10.1128/MCB.21.14.4684
Isola J, Helin H, Kallioniemi OP (1990) Immunoelectron-microscopic localization of a proliferation-associated antigen Ki-67 in MCF-7 cells. Histochem J 22(9):498–506. https://doi.org/10.1007/BF01007235
Jacobs S, Sepideh K (2002) Structure of the HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Nature 295(5562):2080–2083. https://doi.org/10.1126/science.1069473
Junk DJ, Vrba L, Watts GS, Oshiro MM, Martinez JD, Futscher BW (2008) Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells. Neoplasia 10(5):450–461. https://doi.org/10.1593/neo.08120
Kametaka A, Takagi M, Hayakawa T, Haraguchi T, Hiraoka Y, Yoneda Y (2002) Interaction of the chromatin compaction-inducing domain (LR domain) of Ki-67 antigen with HP1 proteins. Genes Cells 7(12):1231–1242. https://doi.org/10.1046/j.1365-2443.2002.00596.x
Kapitein LC, Peterman EJG, Kwok BH, Kim JH, Kapoor TM, Schmidt CF (2005) The biplolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature 435(7038):114–118. https://doi.org/10.1038/nature03493.Published
Kausch I, Lingnau A, Endl E, Sellmann K, Deinert I, Ratliff TL, Jocham D, Sczakiel G, Gerdes J, Böhle A (2003) Antisense treatment against Ki-67 mRNA inhibits proliferation and tumor growth in vitro and in vivo. Int J Cancer 105(5):710–716. https://doi.org/10.1002/ijc.11111
Kill IR (1996) Localisation of the Ki-67 antigen within the nucleolus. Evidence for a fibrillarin-deficient region of the dense fibrillar component. J Cell Sci 109:1253–1263
Kreitz S, Fackelmayer FO, Gerdes J, Knippers R (2000) The proliferation-specific human Ki-67 protein is a constituent of compact chromatin. Exp Cell Res 261(1):284–292. https://doi.org/10.1006/excr.2000.5064
Kumar GS, Gokhan E, De Munter S, Bollen M, Vagnarelli P, Peti W, Page R (2016) The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism. elife 5:e16539. https://doi.org/10.7554/eLife.16539
Lachner M, Carroll D, Rea S et al (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410(6824):116–120. https://doi.org/10.1038/35065132
Larson AG, Elnatan D, Keenen MM, Trnka MJ, Johnston JB, Burlingame AL, Agard DA, Redding S, Narlikar GJ (2017) Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547(7662):236–240. https://doi.org/10.1038/nature22822
Leroy B, Girard L, Hollestelle A, Minna JD, Gazdar AF, Soussi T (2014) Analysis of TP53 mutation status in human cancer cell lines: a reassessment. Hum Mutat 35(6):756–765. https://doi.org/10.1002/humu.22556.Analysis
Li VSW, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, Mohammed S, Heck AJR, Maurice MM, Mahmoudi T, Clevers H (2012) Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 149(6):1245–1256. https://doi.org/10.1016/j.cell.2012.05.002
Lin TC, Su CY, Wu PY, Lai TC, Pan WA, Jan YH, Chang YC, Yeh CT, Chen CL, Ger LP, Chang HT, Yang CJ, Huang MS, Liu YP, Lin YF, Shyy JYJ, Tsai MD, Hsiao M (2016) The nucleolar protein NIFK promotes cancer progression via ck1α/β-catenin in metastasis and ki-67-dependent cell proliferation. elife 5:e11288. https://doi.org/10.7554/eLife.11288
Llères D, James J, Swift S, Norman DG, Lamond AI (2009) Quantitative analysis of chromatin compaction in living cells using FLIM-FRET. J Cell Biol 187(4):481–496. https://doi.org/10.1083/jcb.200907029
Lopez F, Belloc F, Lacombe F, Dumain P, Reiffers J, Bernard P, Boisseau MR (1991) Modalities of synthesis of Ki67 antigen during the stimulation of lymphocytes. Cytometry 12(1):42–49. https://doi.org/10.1002/cyto.990120107
Luo Y, Ren F, Liu Y, Shi Z, Tan Z, Xiong H, Dang Y, Chen G (2015) Clinicopathological and prognostic significance of high Ki-67 labeling index in hepatocellular carcinoma patients: a meta-analysis. Int J Clin Exp Med 8(7):10235–10247
MacCallum DE, Hall PA (1999) Biochemical characterization of pKi67 with the identification of a mitotic-specific form associated with hyperphosphorylation and altered DNA binding. Exp Cell Res 252(1):186–198. https://doi.org/10.1006/excr.1999.4600
Margueron R, Reinberg D (2011) The polycomb complex PRC2 and its mark in life. Nature 469(7330):343–349. https://doi.org/10.1038/nature09784
Matheson TD, Kaufman PD (2015) Grabbing the genome by the NADs. Chromosoma 125(3):361–371. https://doi.org/10.1007/s00412-015-0527-8
Matheson TD, Kaufman PD (2017) The p150N domain of chromatin assembly factor-1 regulates Ki-67 accumulation on the mitotic perichromosomal layer. Mol Biol Cell 28(1):21–29. https://doi.org/10.1091/mbc.E16-09-0659
Mitchison T, Maddox P, Gaetz J et al (2005) Role of polymerization dynamics, opposed motors, and a tensile element in governing the length of Xenopus extract meitotic spindles. Mol Biol Cell 16(6):3064–3076. https://doi.org/10.1091/mbc.E05-02-0174
Mohammad F, Pandey RR, Nagano T, Chakalova L, Mondal T, Fraser P, Kanduri C (2008) Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region. Mol Cell Biol 28(11):3713–3728. https://doi.org/10.1128/MCB.02263-07
Moore JD, Yang J, Truant R, Kornbluth S (1999) Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. J Cell Biol 144(2):213–224. https://doi.org/10.1083/jcb.144.2.213
Murzina N, Verreault A, Laue E, Stillman B (1999) Heterochromatin dynamics in mouse cells: interaction between chromatin assembly factor 1 and HP1 proteins. Mol Cell 4(4):529–540. https://doi.org/10.1016/S1097-2765(00)80204-X
Németh A, Conesa A, Santoyo-Lopez J, Medina I, Montaner D, Péterfia B, Solovei I, Cremer T, Dopazo J, Längst G (2010) Initial genomics of the human nucleolus. PLoS Genet 6(3):e1000889. https://doi.org/10.1371/journal.pgen.1000889
Nielsen PR, Nietlispach D, Mott HR, Callaghan J, Bannister A, Kouzarides T, Murzin AG, Murzina NV, Laue ED (2002) Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416(6876):103–107. https://doi.org/10.1038/nature722
Norton JT, Wang C, Gjidoda A, Henry RW, Huang S (2009) The perinucleolar compartment is directly associated with DNA. J Biol Chem 284(7):4090–4101. https://doi.org/10.1074/jbc.M807255200
Pan W, Tsai H, Wang S et al (2015) The RNA recognition motif of NIFK is required for rRNA maturation during cell cycle progression. RNA Biol 12(3):255–267. https://doi.org/10.1080/15476286.2015.1017221
Pasini D, Bracken AP, Jensen MR, Denchi EL, Helin K (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23(20):4061–4071. https://doi.org/10.1038/sj.emboj.7600402
Pezzilli R, Partelli S, Cannizzaro R, Pagano N, Crippa S, Pagnanelli M, Falconi M (2016) Ki-67 prognostic and therapeutic decision driven marker for pancreatic neuroendocrine neoplasms (PNENs): a systematic review. Adv Med Sci 61(1):147–153. https://doi.org/10.1016/j.advms.2015.10.001
Pyo JS, Kang G, Sohn JH (2015) Ki-67 labeling index can be used as a prognostic marker in gastrointestinal stromal tumor: a systematic review and meta-analysis. Int J Biol Markers 31(2):0. https://doi.org/10.5301/jbm.5000183
Qian J, Lesage B, Beullens M, van Eynde A, Bollen M (2011) PP1/repo-man dephosphorylates mitotic histone H3 at T3 and regulates chromosomal aurora B targeting. Curr Biol 21(9):766–773. https://doi.org/10.1016/j.cub.2011.03.047
Rebelo S, Santos M, Martins F, da Cruz e Silva EF, da Cruz e Silva OAB (2015) Protein phosphatase 1 is a key player in nuclear events. Cell Signal 27(12):2589–2598. https://doi.org/10.1016/j.cellsig.2015.08.007
Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht BD (2002) E2F integrates cell cycle progression with DNA repair, replication, and E2F integrates cell cycle progression with DNA repair, replication, and G 2/M checkpoints. Genes Dev 16(2):245–256. https://doi.org/10.1101/gad.949802
Richards-Taylor S, Ewings SM, Jaynes E, Tilley C, Ellis SG, Armstrong T, Pearce N, Cave J (2015) The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis. J Clin Pathol 69(7):612–618. https://doi.org/10.1136/jclinpath-2015-203340
Saiwaki T, Kotera I, Sasaki M, Takagi M, Yoneda Y (2005) In vivo dynamics and kinetics of pKi-67: transition from a mobile to an immobile form at the onset of anaphase. Exp Cell Res 308(1):123–134. https://doi.org/10.1016/j.yexcr.2005.04.010
Saksouk N, Simboeck E, Déjardin J (2015) Constitutive heterochromatin formation and transcription in mammals. Epigenetics Chromatin 8(1):3. https://doi.org/10.1186/1756-8935-8-3
Schluter C, Duchrow M, Wohlenberg C et al (1993) The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol 123(3):513–522. https://doi.org/10.1083/jcb.123.3.513
Schmidt MHH, Broll R, Bruch HP, Bögler O, Duchrow M (2003) The proliferation marker pKi-67 organizes the nucleolus during the cell cycle depending on ran and cyclin B. J Pathol 199(1):18–27. https://doi.org/10.1002/path.1221
Schmidt MHH, Broll R, Bruch HP, Finniss S, Bögler O, Duchrow M (2004) Proliferation marker pKi-67 occurs in different isoforms with various cellular effects. J Cell Biochem 91(6):1280–1292. https://doi.org/10.1002/jcb.20016
Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182(3):311–322. https://doi.org/10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9
Scholzen T, Endl E, Wohlenberg C, van der Sar S, Cowell IG, Gerdes J, Singh PB (2002) The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure. J Pathol 196(2):135–144. https://doi.org/10.1002/path.1016
Smith CL, Matheson TD, Trombly DJ, Sun X, Campeau E, Han X, Yates JR, Kaufman PD (2014) A separable domain of the p150 subunit of human chromatin assembly factor-1 promotes protein and chromosome associations with nucleoli. Mol Biol Cell 25(18):2866–2881. https://doi.org/10.1091/mbc.E14-05-1029
Sobecki M, Mrouj K, Camasses A, Parisis N, Nicolas E, Llères D, Gerbe F, Prieto S, Krasinska L, David A, Eguren M, Birling MC, Urbach S, Hem S, Déjardin J, Malumbres M, Jay P, Dulic V, Lafontaine DLJ, Feil R, Fisher D (2016) The cell proliferation antigen Ki-67 organises heterochromatin. elife 5:e13722. https://doi.org/10.7554/eLife.13722
Sobecki M, Mrouj K, Colinge J, Gerbe F, Jay P, Krasinska L, Dulic V, Fisher D (2017) Cell cycle regulation accounts for variability in Ki-67 expression levels. Cancer Res 77(10):2722–2734. https://doi.org/10.1158/0008-5472.CAN-16-0707
Starborg M, Gell K, Brundell E, Höög C (1996) The murine Ki-67 cell proliferation antigen accumulates in the nucleolar and heterochromatic regions of interphase cells and at the periphery of the mitotic chromosomes in a process essential for cell cycle progression. J Cell Sci 109(Pt1):143–153
Strohner R, Németh A, Nightingale KP et al (2004) Recruitment of the nucleolar remodeling complex NoRC establishes ribosomal DNA silencing in chromatin. Mol Cell Biol 24(4):1791–1798. https://doi.org/10.1128/MCB.24.4.1791-1798.2004
Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X, Karpen GH (2017) Phase separation drives heterochromatin domain formation. Nature 547(7662):241–245. https://doi.org/10.1038/nature22989
Sueishi M, Takagi M, Yoneda Y (2000) The forkhead-associated domain of Ki-67 antigen interacts with the novel kinesin-like protein Hklp2. J Biol Chem 275(37):28888–28892. https://doi.org/10.1074/jbc.M003879200
Sun X, Bizhanova A, Matheson TD, Yu J, Zhu LJ, Kaufman PD (2017) Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells. Mol Cell Biol 37(17):e00569–e00516. https://doi.org/10.1128/MCB.00569-16
Takagi M, Matsuoka Y, Kurihara T, Yoneda Y (1999) Chmadrin: a novel Ki-67 antigen-related perichromosomal protein possibly implicated in higher order chromatin structure. J Cell Sci 112(Pt 15):2463–2472
Takagi M, Sueishi M, Saiwaki T, Kametaka A, Yoneda Y (2001) A novel nucleolar protein, NIFK, interacts with the forkhead associated domain of Ki-67 antigen in mitosis. J Biol Chem 276(27):25386–25391. https://doi.org/10.1074/jbc.M102227200
Takagi M, Nishiyama Y, Taguchi A, Imamoto N (2014) Ki67 antigen contributes to the timely accumulation of protein phosphatase 1γ on anaphase chromosomes. J Biol Chem 289(33):22877–22887. https://doi.org/10.1074/jbc.M114.556647
Takagi M, Natsume T, Kanemaki MT, Imamoto N (2016) Perichromosomal protein Ki67 supports mitotic chromosome architecture. Genes Cells 21(10):1113–1124. https://doi.org/10.1111/gtc.12420
Takagi M, Ono T, Natsume T, et al (2017) Ki-67 and condensins support the integrity of mitotic chromosomes through distinct mechanisms. bioRxiv. https://doi.org/10.1101/202390
Tanenbaum ME, Macůrek L, Galjart N, Medema RH (2008) Dynein, Lis1 and CLIP-170 counteract Eg5-dependent centrosome separation during bipolar spindle assembly. EMBO J 27(24):3235–3245. https://doi.org/10.1038/emboj.2008.242
Tian H, Qian GW, Li W, Chen FF, Di JH, Zhang BF, Pei DS, Ma P, Zheng JN (2011) A critical role of Sp1 transcription factor in regulating the human Ki-67 gene expression. Tumor Biol 32(2):273–283. https://doi.org/10.1007/s13277-010-0119-4
Trinkle-Mulcahy L, Andersen J, Yun WL et al (2006) Repo-man recruits PP1 to chromatin and is essential for cell viability. J Cell Biol 172(5):679–692. https://doi.org/10.1083/jcb.200508154
Vagnarelli P, Ribeiro S, Sennels L, Sanchez-Pulido L, de Lima Alves F, Verheyen T, Kelly DA, Ponting CP, Rappsilber J, Earnshaw WC (2011) Repo-man coordinates chromosomal reorganization with nuclear envelope reassembly during mitotic exit. Dev Cell 21(2):328–342. https://doi.org/10.1016/j.devcel.2011.06.020
Van Hooser AA, Yuh P, Heald R (2005) The perichromosomal layer. Chromosoma 114(6):377–388. https://doi.org/10.1007/s00412-005-0021-9
van Koningsbruggen S, Gierlinski M, Schofield P, Martin D, Barton GJ, Ariyurek Y, den Dunnen JT, Lamond AI (2010) High-resolution whole-genome sequencing reveals that specific chromatin domains from most human chromosomes associate with nucleoli. Mol Biol Cell 21(21):3735–3748. https://doi.org/10.1091/mbc.E10-06-0508
Vanneste D, Takagi M, Imamoto N, Vernos I (2009) The role of Hklp2 in the stabilization and maintenance of spindle bipolarity. Curr Biol 19(20):1712–1717. https://doi.org/10.1016/j.cub.2009.09.019
Verheijen R, Kuijpers HJ, Schlingemann RO et al (1989a) Ki-67 detects a nuclear matrix-associated proliferation-related antigen. I. Intracellular localization during interphase. J Cell Sci 92(Pt 1):123–130
Verheijen R, Kuijpers HJ, van Driel R et al (1989b) Ki-67 detects a nuclear matrix-associated proliferation-related antigen. II. Localization in mitotic cells and association with chromosomes. J Cell Sci 92(Pt 4):531–540
Waga S, Stillman B (1998) Cyclin-dependent kinase inhibitor p21 modulates the DNA primer-template recognition complex. Mol Cell Biol 18(7):4177–4187. https://doi.org/10.1128/MCB.18.7.4177
Weintraub SJ, Prater CA, Dean DC (1992) Retinoblastoma protein swithes the E2F site from positive to negative element. Nature 358(6383):259–261. https://doi.org/10.1038/358259a0
Wittmann T, Boleti H, Antony C, Karsenti E, Vernos I (1998) Localization of the kinesin-like protein Xklp2 to spindle poles requires a leucine zipper, a microtubule-associated protein, and dynein. J Cell Biol 143(3):673–685. https://doi.org/10.1083/jcb.143.3.673
Yang F, Deng X, Ma W, Berletch JB, Rabaia N, Wei G, Moore JM, Filippova GN, Xu J, Liu Y, Noble WS, Shendure J, Disteche CM (2015) The lncRNA firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biol 16(1). https://doi.org/10.1186/s13059-015-0618-0
Zhang LF, Huynh KD, Lee JT (2007) Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing. Cell 129(4):693–706. https://doi.org/10.1016/j.cell.2007.03.036
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We thank Timothy Matheson for the use of Fig. 2.
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This study was funded by the National Institutes of Health (grant number 1U01 DA040588).
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Sun, X., Kaufman, P.D. Ki-67: more than a proliferation marker. Chromosoma 127, 175–186 (2018). https://doi.org/10.1007/s00412-018-0659-8
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DOI: https://doi.org/10.1007/s00412-018-0659-8