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Cyclin D3 accumulation and activity integrate and rank the comitogenic pathways of thyrotropin and insulin in thyrocytes in primary culture

Oncogene volume 18, pages 7351–7359 (1999)Cite this article

Abstract

The proliferation of most normal cells depends on the synergistic interaction of several growth factors and hormones, but the cell cycle basis for this combined requirement remains largely uncharacterized. We have addressed the question of the requirement for insulin/IGF-1 also observed in many cell culture systems in the physiologically relevant system of primary cultures of dog thyroid epithelial cells stimulated by TSH, which exerts its mitogenic activity only via cAMP. The induction of cyclin A and cdc2, the phosphorylation of cdk2, the nuclear translocation of cdk4 and the assembly of cyclin D3-cdk4 complexes required the synergy of TSH and insulin. Cyclin D3 (the most abundant cyclin D) was necessary for the proliferation stimulated by TSH in the presence of insulin as shown by microinjection of a neutralizing antibody. Cyclin D3 accumulation and activity were differentially regulated by insulin and TSH, which points out this cyclin as an integrator that ranks these comitogenic pathways as supportive and activatory, respectively. Paradoxically TSH alone strongly repressed cyclin D3 accumulation. This inhibition was overridden by insulin, which markedly stimulated cyclin D3 mRNA and protein accumulation, but failed to assemble cyclin D3-cdk4 complexes in the absence of TSH. TSH unmasked the DCS-22 epitope of cyclin D3 and assembled cyclin D3-cdk4 in the presence of insulin. These data demonstrate that cyclin D synthesis and cyclin D-cdk assembly can be dissociated and complementarily regulated by different agents and signalling pathways.

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References

  • Baptist M, Dumont JE and Roger PP. . 1995 Exp. Cell Res. 221: 160–171.

  • Baptist M, Lamy F, Gannon J, Hunt T, Dumont JE and Roger PP. . 1996 J. Cell Physiol. 166: 256–273.

  • Barnes D and Sato G. . 1980 Cell 22: 649–655.

  • Bartek J, Bartkova J and Lukas J. . 1996 Curr. Opin. Cell Biol. 8: 805–814.

  • Bartkova J, Lukas J, Strauss M and Bartek J. . 1998 Oncogene 17: 1027–1037.

  • Baserga R, Sell C, Porcu P and Rubini M. . 1994 Cell Prolif. 27: 63–71.

  • Burikhanov R, Coulonval K, Pirson I, Lamy F, Dumont JE and Roger PP. . 1996 J. Biol. Chem. 271: 29400–29406.

  • Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM and Sherr CJ. . 1999 EMBO J. 18: 1571–1583.

  • Cheung NW, Lou JC and Boyages SC. . 1996 J. Clin. Endocrinol. Metab. 81: 1179–1183.

  • Coppee F, Depoortere F, Bartek J, Ledent C, Parmentier M and Dumont JE. . 1998 Oncogene 17: 631–641.

  • Coulonval K, Maenhaut C, Dumont JE and Lamy F. . 1997 Exp. Cell Res. 233: 395–398.

  • de Asua L, O'Farrell MK, Clingan D and Rudland PS. . 1977 Proc. Natl. Acad. Sci. USA 74: 3845–3849.

  • Deleu S, Pirson I, Clermont F, Nakamura T, Dumont JE and Maenhaut C. . 1999a J. Cell Physiol. in press.

  • Deleu S, Pirson I, Coulonval K, Drouin A, Taton M, Clermont F, Roger PP, Nakamura T, Dumont JE and Maenhaut C. . 1999b Mol. Cell. Endocrinol. 149: 41–51.

  • Depoortere F, Dumont JE and Roger PP. . 1996 J. Cell Sci. 109: 1759–1764.

  • Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP and Dremier S. . 1998 J. Cell Biol. 140: 1427–1439.

  • Diehl JA, Cheng M, Roussel MF and Sherr CJ. . 1998 Genes Dev. 12: 3499–3511.

  • Diehl JA and Sherr CJ. . 1997 Mol. Cell. Biol. 17: 7362–7374.

  • Dremier S, Pohl V, Poteet-Smith C, Roger PP, Corbin J, Doskeland SO, Dumont JE and Maenhaut C. . 1997 Mol. Cell. Biol. 17: 6717–6726.

  • Dumont JE, Lamy F, Roger P and Maenhaut C. . 1992 Physiol. Rev. 72: 667–697.

  • Gerard CM, Lefort A, Christophe D, Libert F, Van Sande J, Dumont JE and Vassart G. . 1989 Mol. Endocrinol. 3: 2110–2118.

  • Gu Y, Rosenblatt J and Morgan DO. . 1992 EMBO J. 11: 3995–4005.

  • Kato JY, Matsuoka M, Polyak K, Massague J and Sherr CJ. . 1994 Cell 79: 487–496.

  • Kelly BL, Wolfe KG and Roberts JM. . 1998 Proc. Natl. Acad. Sci. USA 95: 2535–2540.

  • LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A and Harlow E. . 1997 Genes Dev. 11: 847–862.

  • Lamy F, Roger P, Lecocq R and Dumont JE. . 1989 J. Cell Physiol. 138: 568–578.

  • Lukas J, Bartkova J and Bartek J. . 1996 Mol. Cell. Biol. 16: 6917–6925.

  • Lukas J, Bartkova J, Welcker M, Petersen OW, Peters G, Strauss M and Bartek J. . 1995 Oncogene 10: 2125–2134.

  • Lukas J, Herzinger T, Hansen K, Moroni MC, Resnitzky D, Helin K, Reed SI and Bartek J. . 1997 Genes Dev. 11: 1479–1492.

  • Lukas J, Pagano M, Staskova Z, Draetta G and Bartek J. . 1994 Oncogene 9: 707–718.

  • Lundberg AS and Weinberg RA. . 1998 Mol. Cell Biol. 18: 753–761.

  • Moore JD, Yang J, Truant R and Kornbluth S. . 1999 J. Cell Biol. 144: 213–224.

  • Ohtani K, DeGregori J and Nevins JR. . 1995 Proc. Natl. Acad. Sci. USA 92: 12146–12150.

  • Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM and Pagano M. . 1995 Mol. Cell. Biol. 15: 2612–2624.

  • Reuse S, Pirson I and Dumont JE. . 1991 Exp. Cell Res. 196: 210–215.

  • Reynisdottir I and Massague J. . 1997 Genes Dev. 11: 492–503.

  • Roger PP, Baptist M and Dumont JE. . 1992 J. Cell Biol. 117: 383–393.

  • Roger PP, Christophe D, Dumont JE and Pirson I. . 1997 Eur. J. Endocrinol. 137: 579–598.

  • Roger PP, Reuse S, Maenhaut C and Dumont JE. . 1995 Vitam. Horm. 51: 59–191.

  • Roger PP, Servais P and Dumont JE. . 1983 FEBS Lett. 157: 323–329.

  • Roger PP, Servais P and Dumont JE. . 1987a J. Cell Physiol. 130: 58–67.

  • Roger PP, Servais P and Dumont JE. . 1987b Exp. Cell Res. 172: 282–292.

  • Roger PP, Taton M, Van Sande J and Dumont JE. . 1988 J. Clin. Endocrinol. Metab. 66: 1158–1165.

  • Rozengurt E. . 1986 Science 234: 161–166.

  • Sherr CJ. . 1994 Cell 79: 551–555.

  • Takada K, Amino N, Tada H and Miyai K. . 1990 J. Clin. Invest. 86: 1548–1555.

  • Takahashi S, Conti M, Prokop C, Van Wyk JJ and Earp HS. . 1991 J. Biol. Chem. 266: 7834–7841.

  • Tassan JP, Schultz SJ, Bartek J and Nigg EA. . 1994 J. Cell Biol. 127: 467–478.

  • Thomas GA, Davies HG and Williams ED. . 1994 J. Pathol. 173: 355–360.

  • Tominaga T, Dela Cruz J, Burrow GN and Meinkoth JL. . 1994 Endocrinology 135: 1212–1219.

  • Tramontano D, Moses AC and Ingbar SH. . 1988 Endocrinology 122: 133–136.

  • Ward AC, Csar XF, Hoffmann BW and Hamilton JA. . 1996 Biochem. Biophys. Res. Commun. 224: 10–16.

  • Weinberg RA. . 1995 Cell 81: 323–330.

  • Welcker M, Lukas J, Strauss M and Bartek J. . 1998 Cancer Res. 58: 5053–5056.

  • Werner H, Adamo M, Roberts CTJ and LeRoith D. . 1994 Vitam. Horm. 48: 1–58.

  • Williams DW, Williams ED and Wynford-Thomas D. . 1988 Br. J. Cancer 57: 535–539.

  • Yamamoto K, Hirai A, Ban T, Saito J, Tahara K, Terano T, Tamura Y, Saito Y and Kitagawa M. . (1996) Endocrinology 137: 2036–2042.

  • Zerfass-Thome K, Schulze A, Zwerschke W, Vogt B, Helin K, Bartek J, Henglein B and Jansen-Durr P. . 1997 Mol. Cell Biol. 17: 407–415.

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Acknowledgements

We thank F Depoortere, S Deleu, S Dremier and C Govaerts for advice and helpful discussions, CJ Sherr for providing mouse D3-type cyclin probe, T Nakamura for the HGF and J Gannon and T Hunt for the cyclin A antibody. This study was supported by the Belgium Program on University Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy programming, and by grants from the National Fund for Scientific Research (FNRS, Belgium), the Caisse Générale d'Epargne et de Retraite, the Danish Cancer Society, and the Nordic Cancer Union. A Van Keymeulen is a fellow of the Fonds pour la Formation à la Recherche dans l'Industrie et l'Agriculture (FRIA), and P Roger is a Research Associate of the FNRS.

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  1. Institute of Interdisciplinary Research, Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, Brussels, B-1070, Belgium

    Alexandra Van Keymeulen, Jacques E Dumont & Pierre P Roger

  2. Division of Cancer Biology, Danish Cancer Society, Copenhagen, DK-2100, Denmark

    Jiri Bartek

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Van Keymeulen, A., Bartek, J., Dumont, J. et al. Cyclin D3 accumulation and activity integrate and rank the comitogenic pathways of thyrotropin and insulin in thyrocytes in primary culture. Oncogene 18, 7351–7359 (1999). https://doi.org/10.1038/sj.onc.1203164

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