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Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells

Oncogene volume 25, pages 4413–4420 (2006)Cite this article

Abstract

Aneuploidy is a fundamental principle of many cancer cells and is mostly related to defects in mitotic segregation of chromosomes. Many solid tumors as well as some preneoplastic lesions have been shown to contain polyploid chromosome numbers. The exact mechanisms behind whole-genome duplications are not known but have been linked to compromised mitotic checkpoint genes. We now report that the telomere checkpoint plays a key role for polyploidy in colon cancer cells. Telomerase suppression by a dominant-negative mutant of hTERT and consecutive telomere dysfunction in wild-type HCT116 colon cancer cells resulted in only minor stable chromosomal alterations. However, higher ploidy levels with up to 350 chromosomes were found when the cell-cycle checkpoint proteins p53 or p21 were absent. These findings indicate that telomere dysfunction in the absence of cell-cycle control may explain the high frequency of alterations in chromosome numbers found in many solid tumors.

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Abbreviations

PD:

population doublings

Q-FISH:

quantitative fluorescence in situ hybridization

TRF:

telomere restriction fragment

FACS:

fluorescence activated cell sorter

GFP:

green fluorescent protein

TFI:

fluorescence intensity of individual telomeres expressed in arbitrary units

ΦNX:

phoenix ampho packaging cells

SA:

senescence associated

CIN:

chromosomal instability

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Acknowledgements

We gratefully acknowledge the excellent technical assistance from I Skatulla. We also thank B Vogelstein for providing the HCT116 cells. In addition, we are indebted to R Weinberg and H Vaziri for providing the retroviral hTERT construct. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 364) (to UM), Deutsche Krebshilfe eV (to PB) and from the European Union (QLG1-CT-1999-01341 and MOL CANCER MED) (to UM and PB).

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Authors and Affiliations

  1. Department of Hematology/Oncology, Freiburg University Medical Center, Freiburg, Germany

    M Pantic, S Zimmermann, H El Daly & U M Martens

  2. Department of Gastroenterology, Freiburg University Medical Center, Freiburg, Germany

    O G Opitz

  3. German Cancer Research Center, Heidelberg, Germany

    S Popp & P Boukamp

Authors
  1. M Pantic
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  2. S Zimmermann
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  7. U M Martens
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Correspondence to U M Martens.

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Pantic, M., Zimmermann, S., El Daly, H. et al. Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells. Oncogene 25, 4413–4420 (2006). https://doi.org/10.1038/sj.onc.1209486

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