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Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer

Oncogene volume 18, pages 1983–1991 (1999)Cite this article

Abstract

D-type cyclins are important cell cycle regulators that promote cellular proliferation in response to growth factors by inactivation of the retinoblastoma protein (Rb). Cyclin D1 has been shown to be overexpressed in several cancer types and to act as an oncogene in breast cancers. As D-type cyclins are rate limiting for progression into S phase, the level at which they accumulate must be carefully regulated. Several mechanisms leading to overexpression of cyclin D1 have been reported including amplification, translocation and stabilization of the mRNA. Here, we present data showing elevated cyclin D1 protein in breast cancer samples in the absence of elevated mRNA level. Further, we found that in these cases, cyclin D3 protein also accumulates and that the coordinate increase in cyclin D1 and D3 occurs in 15% (7/47) of breast cancers. In addition we show that blocking the activity of the 26S proteosome results in the accumulation of cyclin D1 and D3, that both D-type cyclins are ubiquitinated and associate with Cul-1, a component of the SCF ubiquitin ligase complex. Finally, we show that the coordinated elevation of cyclin D1 and D3 is also observed in the breast cell line MCF-7 and demonstrate that the degradation of cyclin D1 and D3 is deficient in this cell line. These results indicate that cyclin D1 and cyclin D3 share a common mechanism of degradation and we propose that the coordinate increase of D-type cyclins observed in primary breast cancers reflects a defect in their proteolysis.

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References

  • Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A and Pestell RG. . 1995 J. Biol. Chem. 270: 23589–23597.

  • Ando K, Ajchenbaum-Cymbalista F and Griffin JD. . 1993 Proc. Natl. Acad. Sci. USA 90: 9571–9575.

  • Bartkova J, Zemanova M and Bartek J. . 1996 Int. J. Cancer 65: 323–327.

  • Bodrug S, Warner B, Bath M, Lindeman G, Harris A and Adams J. . 1994 EMBO. J. 13: 2124–2130.

  • Brooks AR, Shiffman D, Chan CS, Brooks EE and Milner PG. . 1996 J. Biol. Chem. 271: 9090–9099.

  • Buckley MF, Sweeney KJE, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CKW, Musgrove EA and Sutherland RL. . 1993 Oncogene 8: 2127–2133.

  • Diehl JA, Zindy F and Sherr CJ. . 1997 Genes Dev. 11: 957–972.

  • Dulic V, Drullinger LF, Lees E, Reed SI and Stein GH. . 1993 PNAS 90: 11034–11038.

  • Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D and Peters G. . 1994 Cancer Res. 54: 1812–1817.

  • Helin K. . 1998 Curr. Opin. Gen. Dev. 8: 28–35.

  • Herber B, Truss M, Beato M and Muller R. . 1994 Oncogene 9: 1295–1304.

  • Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ and Look AT. . 1992 Genomics 13: 565–574.

  • Irniger S, Piatti S, Michaelis C and Nasmyth K. . 1995 Cell 81: 269–277.

  • Kato J-Y and Sherr CJ. . 1993 Proc. Natl. Acad. Sci. USA 90: 11513–11517.

  • Kipreos ET, Lander LE, Wing JP, He WW and Hedgecock EM. . 1996 Cell 85: 829–839.

  • Kranenburg O, Van der Eb AJ and Zantema A. . 1996 EMBO 15: 46–54.

  • Krek W. . 1998 Curr. Opin. Gen. Dev. 8: 36–42.

  • Lammie GA and Peters G. . 1991 Cancer Cells 3: 413–420.

  • Lebwohl DE, Muise-Helmericks R, Sepp-Lorenzino L, Serve S, Timaul M, Bol R, Borgen P and Rosen N. . 1994 Oncogene 9: 1925–1929.

  • Lisztwan J, Marti A, Sutterluty H, Gstaiger M, Wirbelauer C and Krek W. . 1998 EMBO 17: 368–383.

  • Loda M, Cukor B, Tam SW., Lavin P, Fiorentino M, Draetta GF, Jessup JM and Pagano M. . 1997 Nat. Med. 3: 231–234.

  • Lundberg AS and Weinberg RA. . 1998 MCB 18: 753–761.

  • Matsushime H, Roussel MF, Ashmun RA and Sherr CJ. . 1991 Cell 65: 701–713.

  • Motokura T and Arnold A. . 1993 Biochem. Biophys. Acta. 1155: 63–78.

  • Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM and Arnold A. . 1991 Nature 350: 512–515.

  • Murray A. . 1995 Cell 81: 149–152.

  • Musgrove EA, Lee CSL, Buckley MF and Sutherland RL. . 1994 Proc. Natl. Acad. Sci. USA 91: 8022–8026.

  • Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, Direnzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M and Ewen ME. . 1997 Mol. Cell. Biol. 17: 5338–5347.

  • Phillip A, Schneider A, Vasrick I, Finke K, Xiong Y, Beach D, Alitalo K and Eilers M. . 1994 Mol. Cell. Biol. 14: 4032–4043.

  • Rao SS and Kohtz DS. . 1995 J. Biol. Chem. 270: 4093–4100.

  • Rosenberg CL, Wong E, Petty EM, Bale AE, Tsujimoto Y, Harris NL and Arnold A. . 1991 Proc. Natl. Acad. Sci. USA 88: 9638–9642.

  • Scheffner M, Huibregtse JM, Vierstra RD and Howley PM. . 1993 Cell 75: 495–505.

  • Sweeney KJ, Sarcevic B, Sutherland RL and Musgrove EA. . 1997 Oncogene 14: 1329–1340.

  • Wang T, Cardiff RD, Zukerberg L, Lees E, Arnold A and Schmidt EV. . 1994 Nature 369: 669–671.

  • Watanabe G, Albanese C, Lee RJ, Reutens A, Vairo G, Henglein B and Pestell RG. . 1998 Mol. Cell. Biol. 18: 3213–3222.

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

  • Welcker M, Lukas J, Strauss M and Bartek J. . 1996 Oncogene 13: 419–425.

  • Willems AR, Lanker S, Patton EE, Craig KL, Nason TF, Mathias N, Kobayashi R, Wittenberg C and Tyers M. . 1996 Cell 86: 453–463.

  • Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K and Meeker TC. . 1991 Mol. Cell. Biol. 11: 4846–4853.

  • Xiong Y, Connolly T, Futcher B and Beach D. . 1991 Cell 65: 691–699.

  • Zwijsen RML, Wientjens E, Klompmaker R, Van der Sman J, Bernards R and Michalides RAAM. . 1997 Cell 88: 405–415.

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Acknowledgements

We thank Drs Michael Henderson and Deon Venter for providing cancer samples. We would also like to thank Drs Matthew O'Connell and David Bowtell for critical reading of this manuscript. DG is a fellow from the National Cancer Institute of Canada (NCIC). This work was supported by a NHMRC grant no. 981080 to DG.

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  1. Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Melbourne, 3000, Victoria, Australia

    Adrian Russell, M Anne Thompson, Joy Hendley, Lyn Trute, Jane Armes & Doris Germain

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Russell, A., Thompson, M., Hendley, J. et al. Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer. Oncogene 18, 1983–1991 (1999). https://doi.org/10.1038/sj.onc.1202511

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