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Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

Oncogene volume 27, pages 976–984 (2008)Cite this article

Abstract

T-box factors play critical roles in embryonic development and have been implicated in cell cycle regulation and cancer. For example, Tbx2 can suppress senescence through a mechanism involving the repression of the cyclin-dependent kinase inhibitors, p19ARF and p21WAF1/CIP1/SDII, and the Tbx2 gene is deregulated in melanoma, breast and pancreatic cancers. In this study, several transformed human lung fibroblast cell lines were shown to downregulate Tbx2. To further investigate the role of Tbx2 in oncogenesis we therefore stably reexpressed Tbx2 in one such cell line. Compared to their parental cells, the resulting Tbx2-expressing cells are larger, with binucleate and lobular nuclei containing double the number of chromosomes. Moreover, these cells had an increase in frequency of several features of genomic instability such as chromosome missegregation, chromosomal rearrangements and polyploidy. While grossly abnormal, these cells still divide and give rise to cells that are resistant to the chemotherapeutic drug cisplatin. Furthermore, this is shown to be neither species nor cell type dependent, as ectopically expressing Tbx2 in a murine melanoma cell line also induce mitotic defects and polyploidy. These results have important implications for our understanding of the role of Tbx2 in tumorigenesis because polyploidy frequently precedes aneuploidy, which is associated with high malignancy and poor prognosis.

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References

  • Andreassen PR, Lacroix FB, Lohez OD, Margolis RL . (2001). Neither p21WAF1 nor 14-3-3σ prevents G2 progression to mitotic catastrophe in human colon carcinoma cells after DNA damage, but p21WAF1 induces stable G1 arrest in resulting tetraploid cells. Cancer Res 61: 7660–7668.

    CAS  Google Scholar 

  • Baroja A, de la Hoz C, Alvarez A, Vielba R, Sarrat R, Arechaga J et al. (1998). Polyploidization and exit from cell cycle of mechanisms of cultured melanoma cell resistance to methotrexate. Life Sci 62: 2275–2282.

    Article  CAS  Google Scholar 

  • Bilican B, Goding CR . (2006). Cell cycle regulation of the T-Box factor tbx2. Exp Cell Res 312: 2358–2366.

    Article  CAS  Google Scholar 

  • Brummelkamp TR, Kortlever RM, Lingbeek M, Trettel F, MacDonald ME, van Lohuizen M et al. (2002). TBX-3, the gene mutated in ulnar-mammary syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem 227: 6567–6572.

    Article  Google Scholar 

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282: 1497–1501.

    Article  CAS  Google Scholar 

  • Butz NV, Campbell CE, Gronostajski RM . (2004). Differentiation target gene activation by Tbx2 and Tbx2VP16: evidence for activation domain-dependent modulation of gene target specificity. Gene 342: 67–76.

    Article  CAS  Google Scholar 

  • Carlson H, Ota S, Campbell CE, Hurlin PJ . (2001). A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Hum Mol Genet 10: 2403–2413.

    Article  CAS  Google Scholar 

  • Carlson H, Ota S, Song Y, Chen Y, Hurlin PJ . (2002). Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation. Oncogene 21: 3827–3835.

    Article  CAS  Google Scholar 

  • Danesi R, De Braud F, Fogli S, De Pas T, Di Paolo A, Curigliano G et al. (2003). Pharmacogenetics of anticancer drug sensitivity in non-small cell lung cancer. Pharmacol Rev 55: 57–103.

    Article  CAS  Google Scholar 

  • Elledge S . (1996). Cell cycle checkpoints: preventing an identity crisis. Science 274: 1664–1671.

    Article  CAS  Google Scholar 

  • Fan W, Huang X, Chen C, Gray J, Huang T . (2004). TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Cancer Res 64: 5132–5139.

    Article  CAS  Google Scholar 

  • Huang X, Tran T, Zhang L, Hatcher R, Zhang P . (2005). DNA damage-induced mitotic catastrophe is mediated by the Chk1-dependent mitotic exit DNA damage checkpoint. Proc Natl Acad Sci USA 102: 1065–1070.

    Article  CAS  Google Scholar 

  • Jacobs JJL, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, Nederlof PM et al. (2000). Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers. Nat Genet 26: 291–299.

    Article  CAS  Google Scholar 

  • Jerome-Majewska LA, Jenkins GP, Ernstoff E, Zindy F, Sherr CJ, Papaioannou VE . (2005). Tbx3, the ulnar-mammary syndrome gene, and Tbx2 interact in mammary gland development through a p19Arf/p53-independent pathway. Dev Dyn 234: 922–933.

    Article  CAS  Google Scholar 

  • Lingbeek ME, Jacobs JJL, van Lohuizen M . (2002). The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem 277: 26120–26127.

    Article  CAS  Google Scholar 

  • Mahlamaki EH, Barlund M, Tanner M, Gorunova L, Hoglund M, Karhu R et al. (2002). Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. Genes Chromosomes Cancer 35: 353–358.

    Article  CAS  Google Scholar 

  • Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE . (2005). T-box genes in vertebrate development. Ann Rev Genet 39: 219–239.

    Article  CAS  Google Scholar 

  • Namba M, Nishitami K, Kimoto T . (1980). Characteristics of WI-38 cells (WI-38 CT-1) transformed by treatment with Co-60 gamma rays. Gann 71: 300–307.

    CAS  PubMed  Google Scholar 

  • Nigg EA . (2002). Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2: 815–825.

    Article  CAS  Google Scholar 

  • Packham E, Brook JD . (2003). T-box genes in human disorders. Hum Mol Genet 12: 37–44.

    Article  Google Scholar 

  • Paulovich AG, Toczyski DP, Hartwell LH . (1997). When checkpoints fail. Cell 88: 315–321.

    Article  CAS  Google Scholar 

  • Priest JH . (1977) In: Medical Cytogenetics and Cell Culture, 2nd edn. Lea and Febiger: Philadelphia, p 118.

    Google Scholar 

  • Prince S, Carreira S, Vance K.W, Abrahams A, Goding CR . (2004). Tbx2 directly represses the expression of the p21 (WAF1) cyclin-dependent kinase inhibitor. Cancer Res 64: 1669–1674.

    Article  CAS  Google Scholar 

  • Prince S, Wiggins T, Hulley PA, Kidson SH . (2003). Stimulation of melanogenesis by tetradecanoylphorbol-13 acetate (TPA) in mouse melanocytes and neural crest cells. Pigment Cell Res 16: 26–34.

    Article  CAS  Google Scholar 

  • Rieder CL, Maiato H . (2004). Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 7: 637–651.

    Article  CAS  Google Scholar 

  • Rothenberg M, Ling V . (1989). Multidrug resistance: molecular biology and clinical relevance. J Natl Cancer Inst 81: 907–910.

    Article  CAS  Google Scholar 

  • Sinclair CS, Adem C, Naderi A, Soderberg CL, Johnson M, Wu K et al. (2002). TBX2 is preferentially amplified in BRCA1- and BRCA2-related breast tumors. Cancer Res 62: 3587–3591.

    CAS  Google Scholar 

  • Storchova Z, Pellman D . (2004). Polyploidy and aneuploidy: implications for genome stability and cancer. Nature Rev Mol Cell Biol 5: 45–54.

    Article  CAS  Google Scholar 

  • Teng H, Davis E, Abrahams A, Parker I, Mowla S, Prince S . (2007). A role for Tbx2 in the regulation of the α2(1) collagen gene in human fibroblasts. J Cell Biochem [E-pub ahead of print, 3 April 2007].

  • Vance K, Carreira S, Brosch G, Goding CR . (2005). Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res 65: 2260–2268.

    Article  CAS  Google Scholar 

  • Wu Z, Earle J, Saito S, Anderson CW, Appella E, Xu Y . (2002). Mutation of mouse p53 Ser23 and the response to DNA damage. Mol Cell Biol 22: 2441–2449.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the following cytogeneticists from the National Health Laboratory Services for assistance with the metaphase spreads and G-banding analysis: Ronnie Smart and Glynnis Shutte (Groote Schuur Hospital), Jeanette Brusnicky (Tygerberg Hospital) and Dr George Rebello (Department of Human Genetics, University of Cape Town). We also thank Professors Sue Kidson, and Dorothy Bennett, Drs Rafiq Omar and Shaheen Mowla, Deeya Ballim and Amaal Abrahams for their critical feedback on this manuscript. This work was supported by grants from the SA Medical Research Council, the National Research Foundation and the University of Cape Town.

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Authors and Affiliations

  1. Division of Cell Biology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Province, South Africa

    E Davis & S Prince

  2. Division of Medical Biochemistry, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, Western Province, South Africa

    H Teng & M I Parker

  3. Signalling and Development Laboratory, Marie Curie Research Institute, Oxted, Surrey, UK

    B Bilican, B Liu, S Carriera & C R Goding

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  1. E Davis
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Correspondence to S Prince.

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Davis, E., Teng, H., Bilican, B. et al. Ectopic Tbx2 expression results in polyploidy and cisplatin resistance. Oncogene 27, 976–984 (2008). https://doi.org/10.1038/sj.onc.1210701

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