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  • Original Paper
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Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2

Abstract

Cyclin A2 is predominantly, but not exclusively, localized in the nucleus from G1/S transition onwards. It is degraded when cells enter mitosis after nuclear envelope breakdown. We previously showed that a fusion protein (S2A) between the hepatitis B virus (HBV) surface antigen protein and a non-degradable fragment of human cyclin A2 (Δ152) resides in the endoplasmic reticulum membranes, escapes degradation and transforms normal rat fibroblasts. The present study investigates whether cytoplasmic cyclin A2 may play a role in oncogenesis. We show that the sequestration of non-degradable cyclin A2-Δ152 by a cellular ER targeting domain (PRL-A2) leads to cell transformation when coexpressed with activated Ha-ras. REF52 cells constitutively expressing PRL-A2 are found to have a high incidence of multinucleate giant cells, polyploidy and abnormal centrosome numbers, giving rise to the nucleation of multipolar spindles. Injection of these cells into athymic nude mice causes tumors, even in the absence of a cooperating Ha-ras oncogene. These results demonstrate that, independently of any viral context, an intracellular redistribution of non-degradable cyclin A2 is capable of deregulating the normal cell cycle to the point where it promotes aneuploidy and cancer.

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References

  • Aaltomaa S, Eskelinen M, Lipponen P . 1999a Prostate 38: 175–182

  • Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjanen K, Kosma VM . 1999b Br. J. Cancer 80: 2001–2007

  • Albrecht JH, Rieland BM, Nelson CJ, Ahonen CL . 1999 Am. J. Physiol. 277: G1207–G1216

  • Allan K, Jordan RC, Ang LC, Taylor M, Young B . 2000 Arch. Pathol. Lab. Med. 124: 216–220

  • Bailly E, Pines J, Hunter T, Bornens M . 1992 J. Cell. Sci. 101: 529–545

  • Berasain C, Patil D, Perara E, Huang SM, Mouly H, Brechot C . 1998 Oncogene 16: 1277–1288

  • Brechot C . 1993 Curr. Opin. Genet. Dev. 3: 11–18

  • Buendia B, Draetta G, Karsenti E . 1992 J. Cell. Biol. 116: 1431–1442

  • Carbonaro-Hall D, Williams R, Wu L, Warburton D, Zeichner-David M, MacDougall M, Tolo V, Hall F . 1993 Oncogene 8: 1649–1659

  • Castro A, Jaumot M, Verges M, Agell N, Bachs O . 1994 Biochem. Biophys. Res. Commun. 201: 1072–1078

  • Coverley D, Pelizon C, Trewick S, Laskey RA . 2000 J. Cell. Sci. 113: 1929–1938

  • Duensing S, Munger K . 2001 Biochem. Biophys. Acta. 2: M81–M88

  • Eble BE, MacRae DR, Lingappa VR, Ganem D . 1987 Mol. Cell. Biol. 7: 3591–3601

  • Faivre J, Frank-Vaillant M, Poulhe R, Mouly H, Brechot C, Sobczak-Thepot J, Jessus C . 2001 FEBBS Lett. 506: 243–248

  • Franza Jr BR, Maruyama K, Garrels JI, Ruley HE . 1986 Cell 44: 409–418

  • Furuno N, den Elzen N, Pines J . 1999 J. Cell. Biol. 147: 295–306

  • Geley S, Kramer E, Gieffers C, Gannon J, Peters JM, Hunt T . 2001 J. Cell. Biol. 153: 137–148

  • Girard F, Strausfeld U, Fernandez A, Lamb NJ . 1991 Cell 67: 1169–1179

  • Grzanka A, Styczynski J . 2001 Neoplasma 48: 112–115

  • Gudas JM, Payton M, Thukral S, Chen E, Bass M, Robinson MO, Coats S . 1999 Mol. Cell. Biol. 19: 612–622

  • Haas K, Johannes C, Geisen C, Schmidt T, Karsunky H, Blass-Kampmann S, Obe G, Moroy T . 1997a Oncogene 15: 2615–2623

  • Haas K, Staller P, Geisen C, Bartek J, Eilers M, Moroy T . 1997b Oncogene 15: 179–192

  • Hall FL, Braun RK, Mihara K, Fung YK, Berndt N, Carbonaro-Hall DA, Vulliet PR . 1991 J. Biol. Chem. 266: 17430–17440

  • Handa K, Yamakawa M, Takeda H, Kimura S, Takahashi T . 1999 Int. J. Cancer 84: 225–233

  • Hildt E, Hofschneider PH . 1998 Recent Results Cancer Res. 154: 315–329

  • Huuhtanen RL, Blomqvist CP, Bohling TO, Wiklund TA, Tukiainen EJ, Virolainen M, Tribukait B, Andersson LC . 1999 Cancer Res. 59: 2885–2890

  • Jacobs HW, Keidel E, Lehner CF . 2001 EMBO J. 20: 2376–2386

  • Kaufmann H, Marone R, Olayioye MA, Bailey JE, Fussenegger M . 2001 J. Biol. Chem. 276: 29987–29993

  • Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R . 1990 Nature 343: 457–461

  • Lauer U, Weiss L, Hofschneider PH, Kekule AS . 1992 J. Virol. 66: 5284–5289

  • Lingappa VR, Chaidez J, Yost CS, Hedgpeth J . 1984 Proc. Natl. Acad. Sci. USA 81: 456–460

  • Lingle WL, Salisbury JL . 2000 Curr. Top. Dev. Biol. 49: 313–329

  • Lu XP, Koch KS, Lew DJ, Dulic V, Pines J, Reed SI, Hunter T, Leffert HL . 1992 J. Biol. Chem. 267: 2841–2842

  • Lukas C, Sorensen CS, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters JM, Bartek J, Lukas J . 1999 Nature 401: 815–818

  • Maridor G, Gallant P, Golsteyn R, Nigg EA . 1993 J. Cell. Sci. 106: 535–544

  • Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA . 1999 Nat. Cell. Biol. 1: 88–93

  • Orend G, Hunter T, Ruoslahti E . 1998 Oncogene 16: 2575–2583

  • Parry DH, O'Farrell PH . 2001 Curr. Biol. 11: 671–683

  • Petersen BO, Lukas J, Sorensen CS, Bartek J, Helin K . 1999 EMBO J. 18: 396–410

  • Pines J . 1999 Nat. Cell. Biol. 1: E73–E79

  • Prange R, Streeck RE . 1995 EMBO J. 14: 247–256

  • Sluder G, Hinchcliffe EH . 1999 Biol. Cell. 91: 413–427

  • Sluder G, Miller FJ, Rieder CL . 1986 J. Cell. Biol. 103: 1873–1881

  • Sorensen CS, Lukas C, Kramer ER, Peters JM, Bartek J, Lukas J . 2001 Mol. Cell. Biol. 21: 3692–3703

  • Soucek T, Yeung RS, Hengstschlager M . 1998 Proc. Natl. Acad. Sci. USA 95: 15653–15658

  • Sprenger F, Yakubovich N, O'Farrell PH . 1997 Curr. Biol. 7: 488–499

  • Thomas L, Clarke PR, Pagano M, Gruenberg J . 1992 J. Biol. Chem. 267: 6183–6187

  • Verges M, Castro A, Jaumot M, Bachs O, Enrich C . 1997 Biochem. Biophys. Res. Commun. 230: 49–53

  • Wang J, Chenivesse X, Henglein B, Brechot C . 1990 Nature 343: 555–557

  • Winston N, Bourgain-Guglielmetti F, Ciemerych MA, Kubiak JZ, Senamaud-Beaufort C, Carrington M, Brechot C, Sobczak-Thepot J . 2000 Dev. Biol. 223: 139–153

  • Wolff A, de Nechaud B, Chillet D, Mazarguil H, Desbruyeres E, Audebert S, Edde B, Gros F, Denoulet P . 1992 Eur. J. Cell. Biol. 59: 425–432

  • Woodman PG, Adamczewski JP, Hunt T, Warren G . 1993 Mol. Biol. Cell. 4: 541–553

  • Yost CS, Hedgpeth J, Lingappa VR . 1983 Cell 34: 759–766

  • Zhai YL, Nikaido T, Shiozawa T, Orii A, Fujii S . 1999 Int. J. Cancer 84: 244–250

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Acknowledgements

We would like to thank all the members of our two laboratories for helpful discussions. We thank C Garcia-Cordier and G Pivert for their technical assistance. We are grateful to Dr P Denoulet for GT335 antibody and to Dr VR Lingappa for pSP Sp+1L.ST.gG. This research was supported by grants from INSERM, CNRS, INRA, University Paris VI, ARC (no. 5899 to C Jessus, no. 9169 to J Sobczak-Thépot and C Bréchot), LNCC.

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Correspondence to Jamila Faivre.

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Faivre, J., Frank-Vaillant, M., Poulhe, R. et al. Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2. Oncogene 21, 1493–1500 (2002). https://doi.org/10.1038/sj.onc.1205215

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