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Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53

Abstract

The exact duplication of chromosomal DNA during each cell cycle ensures the correct inheritance of genetic material from mother to daughter cells. In eukaryotic cells, DNA replication can occur only when the origin of DNA replication is accurately marked by a group of proteins termed licensing proteins. One such protein is Cdt1, which is recruited first to the origin of DNA replication followed by cell division cycle 6 (Cdc6) and mini-chromosome maintenance proteins (Mcms). We previously reported that NIH3T3 cells overexpressing Cdt1 readily formed tumors in mice. To further investigate its oncogenic mechanism, we generated transgenic mice expressing Cdt1 in thymocytes. Our studies demonstrated that T-cell-directed Cdt1 transgenic mice showed normal T-cell development. However, such transgenic mice developed thymic lymphoblastic lymphoma when crossed with p53 null mice. Furthermore, tumor cells derived from NIH3T3 cells overexpressing Cdt1 displayed numerical and structural chromosomal aberrations in the form of ploidy, double minutes, translocation, inversion, chromosome end-to-end fusion and robertsonian mutation. Collectively, our studies suggest that Cdt1 overexpression most likely contributes to tumorigenecity by causing genomic instability.

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Acknowledgements

We thank Laura Wells and Michael White for help with mice, Wen Jie Zhang for help with flow cytometry, Herbert W Virgin for p53-deficient mice, Robert Schreiber for the p1017 plasmid, and Jason Weber for p19/ARF and p27 antibodies. We also thank Paul Allen and Lee Ratner for helpful discussion, Laura Mandik-Nayak and Wanghai Zhang for help with immunohistochemistry, and Changwon Park and Jesse Lugus for helpful comments on the manuscript. This work was supported by Grants NS34746 and CA10445-Project 2, Department of Army (TKP) and RTI04-03-05, the Regional Technology Innovation Program of MOCIE, and KMOST 2005-01112, KOSEF (EM).

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Correspondence to Kyunghee Choi.

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Seo, J., Chung, Y., Sharma, G. et al. Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53. Oncogene 24, 8176–8186 (2005). https://doi.org/10.1038/sj.onc.1208881

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Keywords

  • Cdt1
  • genomic instability
  • p53
  • cancer

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