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Cyclin E in breast tumors is cleaved into its low molecular weight forms by calpain

Oncogene volume 22, pages 769–774 (2003)Cite this article

Abstract

Abundant levels of the hyperactive low molecular weight (LMW) forms of cyclin E contribute to deregulation of Cdk2 in breast tumors, but the mechanism through which they arise is not fully understood. Here, we explored the hypothesis that post-translational processing by a protease generates the LMW forms of cyclin E in breast tumors. In ZR75 tumor cell lysates, calcium-induced cyclin E truncation into peptides corresponding in size with LMW forms of cyclin E in tumor tissues. Calpeptin inhibited calcium-stimulated cyclin E truncation, indicating that cleavage resulted from activity of the calcium-dependent protease, calpain. Consistently, calcium+calpain caused truncation of cyclin E immunoprecipitated from tumor cells and tissues. Calcium also caused truncation of the calpain regulatory subunit in tumor cell lysates, indicating that elevated calpain activity accompanies cyclin E truncation. Increased levels of the calpain small subunit were also observed in breast tumors, and significant amounts of its proteolyzed forms indicated increased calpain activity. While elastase also caused cyclin E truncation, the cleavage pattern was distinct from that generated by calpain, suggesting discrete mechanisms in regulating the formation of LMW cyclin E in breast tumors. Treatment of ZR75 cultures with calcium+A23187 recapitulated the formation of the calcium/calpain-induced LMW forms of cyclin E. Altered calcium homeostasis and/or inability of the endogenous calpain inhibitor to control the activity of high levels of the calpain small subunit may contribute to increased calpain activity in breast tumors, causing abundant levels of LMW cyclin E.

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References

  • Bradford MM . (1976). Anal. Biochem., 72, 248–254.

  • Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA and Sutherland RL . (1993). Oncogene, 8, 2127–2133.

  • Croall DE and DeMartino GN . (1991). Physiol. Rev., 71, 813–847.

  • Dou QP, Pardee AB and Keyomarsi K . (1996). Nat. Med. 2, 254.

  • Ford HL, Kabingu EN, Bump EA, Mutter GL and Pardee AB . (1998). Proc. Natl. Acad. Sci. USA, 95, 12608–12613.

  • Harwell RM, Porter DC, Danes C and Keyomarsi K . (2000). Cancer Res., 60, 481–489.

  • Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI and Weinberg RA . (1992). Cell, 70, 993–1006.

  • Kawasaki H and Kawashima S . (1996). Mol. Membr. Biol., 13, 217–224.

  • Keyomarsi K, Conte D, Toyofuku W and Fox MP . (1995). Oncogene, 11, 941–950.

  • Keyomarsi K and Herliczek TW . (1997). Prog. Cell Cycle Res., 3, 171–191.

  • Keyomarsi K and Pardee AB . (1993). Proc. Natl. Acad. Sci. USA, 90, 1112–1116.

  • Lee SW, Tomasetto C, Swisshelm K, Keyomarsi K and Sager R . (1992). Proc. Natl. Acad. Sci. USA, 89, 2504–2508.

  • Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, Lowen D, Javni J, Miller FR, Slavin J and Anderson RL . (1999). Clin. Exp. Metastasis, 17, 163–170.

  • Nielsen NH, Arnerlov C, Emdin SO and Landberg G . (1996). Br. J. Cancer, 74, 874–880.

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

  • Porter DC, Zhang N, Danes C, McGahren MJ, Harwell RM, Faruki S and Keyomarsi K . (2001). Mol. Cell Biol., 21, 6254–6269.

  • Said TK and Medina D . (1995). Carcinogenesis, 16, 823–830.

  • Saido TC, Sorimachi H and Suzuki K . (1994). FASEB J., 8, 814–822.

  • Sewing A, Ronicke V, Burger C, Funk M and Muller R . (1994). J. Cell Sci., 107, 581–588.

  • Shiba E, Kambayashi JI, Sakon M, Kawasaki T, Kobayashi T, Koyama H, Yayoi E, Takatsuka Y and Takai SI . (1996). Breast Cancer, 3, 13–17.

  • Steeg PS and Zhou Q . (1998). Breast Cancer Res. Treat., 52, 17–28.

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Acknowledgements

We thank Dr Martha Stampfer for providing the breast tumor tissues and HMEC, and Deirdre Lobb for technical assistance. This work was supported by an operating grant from the Canadian Institutes of Health Research to KYL, an Alberta Heritage Foundation for Medical Research Scholar.

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  1. Xu Dong Wang

    Present address: Department of Physiology/Cancer Biology Research Group, Guiyang Medical College, 9 Beijing Road, Guiyang, Guizhou, 550004, China

Authors and Affiliations

  1. Department of Cell Biology and Anatomy, Cancer Biology and Neuroscience Research Groups, The University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    Xu Dong Wang, Jesusa L Rosales, Anthony Magliocco, Ruban Gnanakumar & Ki-Young Lee

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  1. Xu Dong Wang
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  2. Jesusa L Rosales
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Correspondence to Ki-Young Lee.

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Wang, X., Rosales, J., Magliocco, A. et al. Cyclin E in breast tumors is cleaved into its low molecular weight forms by calpain. Oncogene 22, 769–774 (2003). https://doi.org/10.1038/sj.onc.1206166

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