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Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation

Abstract

The centrosomes are thought to maintain genomic stability through the establishment of bipolar spindles during cell division, ensuring equal segregation of replicated chromosomes to two daughter cells. Deregulated duplication and distribution of centrosomes have been implicated in chromosome segregation abnormalities, leading to aneuploidy seen in many cancer cell types. Here, we report that STK15 (also known as BTAK and aurora2 ), encoding a centrosome-associated kinase, is amplified and overexpressed in multiple human tumour cell types, and is involved in the induction of centrosome duplication-distribution abnormalities and aneuploidy in mammalian cells. STK15 amplification has been previously detected in breast tumour cell lines 1 and in colon tumours 2 ; here, we report its amplification in approximately 12% of primary breast tumours, as well as in breast, ovarian, colon, prostate, neuroblastoma and cervical cancer cell lines. Additionally, high expression of STK15 mRNA was detected in tumour cell lines without evidence of gene amplification. Ectopic expression of STK15 in mouse NIH 3T3 cells led to the appearance of abnormal centrosome number (amplification) and transformation in vitro . Finally, overexpression of STK15 in near diploid human breast epithelial cells revealed similar centrosome abnormality, as well as induction of aneuploidy. These findings suggest that STK15 is a critical kinase-encoding gene, whose overexpression leads to centrosome amplification, chromosomal instability and transformation in mammalian cells.

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Figure 1: Southern- and northern-blot hybridization analyses estimating STK15 copy number (a) and STK15 mRNA expression (b) in tumour cell lines.
Figure 2: Dual colour FISH demonstrating localization of the STK15 probe (green signals) along with chromosome-20-specific centromeric probe or a 'p' arm-specific probe (red signals) on normal human chromosome 20 (a,b) and diploid copy number of STK15 in the interphase nucleus of normal breast epithelial tissue (c).
Figure 3: Expression of STK15 and kinase activity.
Figure 4: Cell lysates from exponentially growing (lane E) or colcemid synchronized mitotic (lane M) HeLa cells were prepared and proteins (50 μg) from each lysate were separated by 12.
Figure 5: STK15 expression and centrosomes in mammalian cells.
Figure 6: FISH localization of centromeres of chromosomes 13, 21 and X in STK15-transfected near-diploid breast epithelial cell line MCF10A.

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References

  1. Sen, S., Zhou, H. & White, R.A. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene. 14, 2195– 2200 (1997).

    Article  CAS  Google Scholar 

  2. Bischoff, R.J. et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17, 3052–3065 (1998).

    Article  CAS  Google Scholar 

  3. Kallioniemi, A. et al. Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc. Natl Acad. Sci. USA 91, 2156–2160 ( 1994).

    Article  CAS  Google Scholar 

  4. Reznikoff, C.A. et al. A molecular genetic model of human bladder cancer pathogenesis. Semin. Oncol. 23, 571– 584 (1996).

    CAS  PubMed  Google Scholar 

  5. Larremendy, M.-L. et al. Gains, losses and amplification of DNA sequences evaluated by comparative genomic hybridization in chrondrosarcomas. Am. J. Pathol. 150, 685–691 ( 1997).

    Google Scholar 

  6. Schlegel, J. et al. Comparative genomic in situ hybridization of colon carcinomas with replication error. Cancer Res. 55, 6002–6005 (1995).

    CAS  PubMed  Google Scholar 

  7. Iwabuchi, H. et al.Genetic analysis of benign, low grade and high grade ovarian tumours. Cancer Res. 55, 6172– 6180 (1995).

    CAS  PubMed  Google Scholar 

  8. Solinas, et al. Mapping of chromosomal imbalances in pancreatic carcinoma by comparative genomic hybridization. Cancer Res. 56, 3803–3807 (1996).

    Google Scholar 

  9. Bockmuhl, U., Petersen, I., Schwendel, A. & Dietel, M. Genetic screening of head and neck carcinomas using comparative genomic hybridization (CGH). Larynogorhinootologie 75, 408– 414 (1996).

    Article  CAS  Google Scholar 

  10. Isola, J.J. et al.Genetic aberrations detected by comparative genomic hybridization predict outcome in node-negative breast cancer. Am. J. Pathol. 147, 905–911 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hanks, S.K. & Hunter, T. FASEB Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).

    Article  CAS  Google Scholar 

  12. Glover, D.M., Leibowitz, M.H., McLean, D.A. & Parry, H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81, 95– 105 (1995).

    Article  CAS  Google Scholar 

  13. Francisco, L., Wang, W. & Chan, C.S. Type 1 protein phosphatase acts in opposition to IpL1 protein kinase in regulating yeast chromosome segregation. Mol. Cell. Biol. 14, 4731–4740 (1994).

    Article  CAS  Google Scholar 

  14. Kimura, M. et al. Cell cycle-dependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1. J. Biol. Chem. 272, 13766– 13771 (1997).

    Article  CAS  Google Scholar 

  15. Yanai, A., Arama, E., Kilfin, G. & Motro, B. ayk1, a novel mammalian gene related to Drosophila aurora centrosome separation kinase, is specifically expressed during meiosis. Oncogene 14, 2943–2950 (1997).

    Article  CAS  Google Scholar 

  16. Gopalan, G., Chan, C.S.M. & Donovan, P.J. A novel mammalian mitotic spindle associated kinase is related to yeast and fly chromosome segregation regulators. J. Cell. Biol. 138, 643–656 (1997).

    Article  CAS  Google Scholar 

  17. Soule, H.D. et al. Isolation and characterization of spontaneously immortalized human breast epithelial cell line MCF-10. Cancer Res. 50, 6075–6086 (1990).

    CAS  PubMed  Google Scholar 

  18. Kellogg, D.R., Oegema, K., Raff, J., Schneider, K. & Alberts, B.M. CP60: a microtubule-associated protein that is localized to the centrosome in a cell cycle-specific manner. Mol. Biol. Cell. 6, 1673–1684 ( 1995).

    Article  CAS  Google Scholar 

  19. Vandre, D.D., Davis, F.M., Rao, P.N. & Borisy, G.G. Phosphoproteins are components of mitotic microtubule organizing centers. Proc. Natl Acad. Sci USA 81, 4439–4443 (1984).

    Article  CAS  Google Scholar 

  20. Verde, F., Berrez, J.M., Antony, C. & Karsenti, E. Taxol-induced microtubule asters in mitotic extracts of Xenopus eggs: requirement for phosphorylated factors and cytoplasmic dynein. J. Cell. Biol. 112, 1177–1187 ( 1991).

    Article  CAS  Google Scholar 

  21. Taagepera, S., Campbell, M.S. & Gorbsky, G.J. Cell-cycle-regulated localization of tyrosine and threonine phosphoepitopes at the kinetochores of mitotic chromosomes. Exp. Cell Res. 221, 249–260 (1995).

    Article  CAS  Google Scholar 

  22. Buendia, B., Draetta, G. & Karsenti, E. Regulation of the microtubule nucleating activity of centrosomes in Xenopus egg extracts: role of cyclin A-associated protein kinase. J. Cell. Biol. 116, 1431– 1442 (1992).

    Article  CAS  Google Scholar 

  23. Fry, A.M., Meraldi, P. & Nigg, E.A. A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators. EMBO J. 17, 470–481 (1998).

    Article  CAS  Google Scholar 

  24. Blangy, A. et al. Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83, 1159– 1169 (1995).

    Article  CAS  Google Scholar 

  25. Lane, H.A. & Nigg, E.A. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J. Cell. Biol. 135, 1701–1713 (1996).

    Article  CAS  Google Scholar 

  26. Wolf, G. et al. Prognostic significance of polo like kinase (PLK) expression in non-small cell lung cancer. Oncogene. 14, 543–549 (1997).

    Article  CAS  Google Scholar 

  27. Smith, M.R. et al. Malignant transformation of mammalian cells initiated by constitutive expression of polo-like kinase. Biochem. Biophys. Res. Commun. 234, 397–405 ( 1997).

    Article  CAS  Google Scholar 

  28. Boveri, T. in The Origin of Malignant Tumours (Williams and Wilkins, Baltimore, 1914).

    Google Scholar 

  29. Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G.F. Abnormal centrosome amplification in the absence of p53. Science 271, 1744– 1747 (1996).

    Article  CAS  Google Scholar 

  30. Wang, X.-T. et al. Expression of p53 mutant in the epidermis of transgenic mice accelerates chemical carcinogenesis. Oncogene 17, 35–45 1998).

    Article  Google Scholar 

  31. Lingle, W.L., Lutz, W.H., Ingle, J.N., Maihle, J.N. & Salisbury, J.L. Centrosome hypertrophy in human breast tumours: Implications for genomic stability and cell polarity. Proc. Natl Acad. Sci. USA 95, 2950–2955 ( 1998).

    Article  CAS  Google Scholar 

  32. Cahill, D.P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 301–303 ( 1998).

    Article  Google Scholar 

  33. Orr-Weaver, T.L. & Weinberg, R.A. A checkpoint on the road to cancer. Nature 392, 223– 224 (1998).

    Article  CAS  Google Scholar 

  34. Zhuang, Z. et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genet. 20, 66–69 ( 1998).

    Article  CAS  Google Scholar 

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Acknowledgements

Authors are grateful to R. Balczon for supplying the auto-antibodies against the centrosome and to R.E. Palazzo for the two rabbit antisera against γ tubulin. Technical assistance of M. Nelman Gonzalez, S. Che, A. Wagh, R. Nandagiri and the help of M. Pearlman in counting the soft agar colonies and S. Zhao in nucleotide sequence analyses are acknowledged. We thank I. Hernandez, L. Benson and D. Sprabary for help in preparing this manuscript and the Department of Scientific Publications at UTMDACC for editorial suggestions. This work was supported in part by grants from the Physicians Referral Service, Breast Cancer Basic Research Program of the University of Texas M.D. Anderson Cancer Center, from NIH (CA 61979) to S.S. and (CA 41424, CA 64255) to B.R.B. The M.D. Anderson DNA sequencing facility is supported by the NIH core grant CA 16672.

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Correspondence to Subrata Sen.

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Zhou, H., Kuang, J., Zhong, L. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20, 189–193 (1998). https://doi.org/10.1038/2496

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