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The CHFR mitotic checkpoint protein delays cell cycle progression by excluding Cyclin B1 from the nucleus

Oncogene volume 24, pages 2589–2598 (2005)Cite this article

Abstract

CHFR, a novel checkpoint gene inactivated in human cancer, delays chromosome condensation in cells treated with microtubule poisons. To understand the molecular mechanism for this delay, we characterized cells with inactivated CHFR and stably transfected derivatives expressing the wild-type gene. After exposure to microtubule poisons, the CHFR-expressing cells arrested transiently in early prophase with a characteristic ruffled morphology of the nuclear envelope and no signs of chromosome condensation. Several markers suggested that Cyclin A/Cdc2 had been activated, whereas Aurora-A and -B and Cyclin B1/Cdc2 were inactive. Further, Cyclin B1 was excluded from the nucleus. Ectopic expression of Cyclin B1 with a mutant nuclear export sequence induced chromosome condensation, and thus overcame the CHFR checkpoint. We conclude that the mechanism by which CHFR delays chromosome condensation involves inhibition of accumulation of Cyclin B1 in the nucleus.

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References

  • Adams RR, Maiato H, Earnshaw WC and Carmena M . (2001). J. Cell Biol., 153, 865–880.

  • Amon A . (1999). Curr. Opin. Genet. Dev., 9, 69–75.

  • Basu J, Bousbaa H, Logarinho E, Li Z, Williams BC, Lopes C, Sunkel CE and Goldberg ML . (1999). J. Cell Biol., 146, 13–28.

  • Beaudouin J, Gerlich D, Daigle N, Eils R and Ellenberg J . (2002). Cell, 108, 83–96.

  • Bertholon J, Wang Q, Falette N, Verny C, Auclair J, Chassot C, Navarro C, Saurin JC and Puisieux A . (2003). Oncogene, 22, 8956–8960.

  • Bothos J, Summers MK, Venere M, Scolnick D and Halazonetis TD . (2003). Oncogene, 22, 7101–7107.

  • Bullough WS and Johnson M . (1951). Proc. R. Soc. Lond. B. Biol. Sci., 138, 562–575.

  • Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW and Vogelstein B . (1998). Nature, 392, 300–303.

  • Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B and Lengauer C . (1999). Genomics, 58, 181–187.

  • Chaturvedi P, Sudaki V, Bobiak ML, Fisher PW, Mattern MR, Jablonski SA, Hurle MR, Zhu Y, Yen TJ and Zhou BB . (2002). Cancer Res., 62, 1797–1801.

  • Corn PG, Summers MK, Fogt F, Virmani AK, Gazdar AF, Halazonetis TD and El-Deiry WS . (2003). Carcinogenesis, 24, 47–51.

  • Dobles M, Liberal V, Scott ML, Benezra R and Sorger PK . (2000). Cell, 101, 635–645.

  • Durocher D, Henckel J, Fersht AR and Jackson SP . (1999). Mol. Cell, 4, 387–394.

  • Elia AE, Cantley LC and Yaffe MB . (2003). Science, 299, 1228–1231.

  • Erson AE and Petty EM . (2004). Mol. Carcinog., 39, 26–33.

  • Georgatos SD, Pyrpasopoulou A and Theodoropoulos PA . (1997). J. Cell Sci., 110, 2129–2140.

  • Giet R and Glover DM . (2001). J. Cell Biol., 152, 669–682.

  • Hagting A, Jackman M, Simpson K and Pines J . (1999). Curr. Biol., 9, 680–689.

  • Hagting A, Karlsson C, Clute P, Jackman M and Pines J . (1998). EMBO J., 17, 4127–4138.

  • Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, Hatakeyama K and Saya H . (2003). Cell, 114, 585–598.

  • Hsu JY, Sun ZW, Li X, Reuben M, Tatchell K, Bishop DK, Grushcow JM, Brame CJ, Caldwell JA, Hunt DF, Lin R, Smith MM and Allis CD . (2000). Cell, 102, 279–291.

  • Jha MN, Bamburg JR and Bedford JS . (1994). Cancer Res., 54, 5011–5015.

  • Jin P, Hardy S and Morgan DO . (1998). J. Cell Biol., 141, 875–885.

  • Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T and Liu YC . (1999). Science, 286, 309–312.

  • Kalitsis P, Earle E, Fowler KJ and Choo KH . (2000). Genes Dev., 14, 2277–2282.

  • Kanda T, Sullivan KF and Wahl GM . (1998). Curr. Biol., 8, 377–385.

  • Kang D, Chen J, Wong J and Fang G . (2002). J. Cell Biol., 156, 249–259.

  • Karlsson C, Katich S, Hagting A, Hoffmann I and Pines J . (1999). J. Cell Biol., 146, 573–584.

  • Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S and Yarden Y . (1999). Mol. Cell, 4, 1029–1040.

  • Li J, Meyer AN and Donoghue DJ . (1997). Proc. Natl. Acad. Sci. USA, 94, 502–507.

  • Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyam S and Weissman AM . (1999). Proc. Natl. Acad. Sci. USA, 96, 11364–11369.

  • Mariatos G, Bothos J, Zacharatos P, Summers MK, Scolnick DM, Kittas C, Halazonetis TD and Gorgoulis VG . (2003). Cancer Res., 63, 7185–7189.

  • Matsusaka T and Pines J . (2004). J. Cell Biol., 166, 507–516.

  • McIntosh JR and Koonce MP . (1989). Science, 246, 622–628.

  • Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, Dobles M, Sorger PK, Murty VV and Benezra R . (2001). Nature, 409, 355–359.

  • Mizuno K, Osada H, Konishi H, Tatematsu Y, Yatabe Y, Mitsudomi T, Fujii Y and Takahashi T . (2002). Oncogene, 21, 2328–2333.

  • Peter M, Heitlinger E, Haner M, Aebi U and Nigg EA . (1991). EMBO J., 10, 1535–1544.

  • Pickart CM . (2001). Mol. Cell, 8, 499–504.

  • Pines J and Hunter T . (1991). J. Cell Biol., 115, 1–17.

  • Rieder CL and Cole R . (2000). Curr. Biol., 10, 1067–1070.

  • Salina D, Bodoor K, Eckley DM, Schroer TA, Rattner JB and Burke B . (2002). Cell, 108, 97–107.

  • Satoh A, Toyota M, Itoh F, Sasaki Y, Suzuki H, Ogi K, Kikuchi T, Mita H, Yamashita T, Kojima T, Kusano M, Fujita M, Hosokawa M, Endo T, Tokino T and Imai K . (2003). Cancer Res., 63, 8606–8613.

  • Schneider U, Mini T, Jeno P, Fisher PA and Stuurman N . (1999). Biochemistry, 38, 4620–4632.

  • Scolnick DM and Halazonetis TD . (2000). Nature, 406, 430–435.

  • Shah JV and Cleveland DW . (2000). Cell, 103, 997–1000.

  • Shibata Y, Haruki N, Kuwabara Y, Ishiguro H, Shinoda N, Sato A, Kimura M, Koyama H, Toyama T, Nishiwaki T, Kudo J, Terashita Y, Konishi S, Sugiur H and Fujii Y . (2002). Carcinogenesis, 23, 1695–1699.

  • Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis TD, Pavletich NP and Jeffrey PD . (2002). Structure, 10, 891–899.

  • Strausfeld U, Fernandez A, Capony JP, Girard F, Lautredou N, Derancourt J, Labbe JC and Lamb NJ . (1994). J. Biol. Chem., 269, 5989–6000.

  • Toyoshima F, Moriguchi T, Wada A, Fukuda M and Nishida E . (1998). EMBO J., 17, 2728–2735.

  • Toyoshima-Morimoto F, Taniguchi E, Shinya N, Iwamatsu A and Nishida E . (2001). Nature, 410, 215–220.

  • Toyota M, Sasaki Y, Satoh A, Ogi K, Kikuchi T, Suzuki H, Mita H, Tanaka N, Itoh F, Issa JP, Jair KW, Schuebel KE, Imai K and Tokino T . (2003). Proc. Natl. Acad. Sci. USA, 100, 7818–7823.

  • Ward GE and Kirschner MW . (1990). Cell, 61, 561–577.

  • Woo RA and Poon RY . (2003). Cell Cycle, 2, 316–324.

  • Yang J, Bardes ES, Moore JD, Brennan J, Powers MA and Kornbluth S . (1998). Genes, Dev., 12, 2131–2143.

  • Yang J, Song H, Walsh S, Bardes ES and Kornbluth S . (2001). J. Biol. Chem., 276, 3604–3609.

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Acknowledgements

We thank G Wahl for the gift of plasmid expressing GFP fused to histone H2B and Daniel Scolnick for helpful discussions. Financial support was provided by the National Cancer Institute (CA89630). MKS and JB were supported by the National Cancer Institute Training Grants CA09677 and CA09171, respectively.

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Authors and Affiliations

  1. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104-4268, USA

    Matthew K Summers, John Bothos & Thanos D Halazonetis

  2. Program in Cell and Molecular Biology, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Matthew K Summers & John Bothos

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Thanos D Halazonetis

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  1. Matthew K Summers
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Correspondence to Thanos D Halazonetis.

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Summers, M., Bothos, J. & Halazonetis, T. The CHFR mitotic checkpoint protein delays cell cycle progression by excluding Cyclin B1 from the nucleus. Oncogene 24, 2589–2598 (2005). https://doi.org/10.1038/sj.onc.1208428

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