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Deregulated Overexpression of hCdt1 and hCdc6 Promotes Malignant Behavior

¹ Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine and ² Department of Biochemistry School of Medicine, University of Athens; ³ Laboratory of Cell Proliferation and Ageing, Institute of Biology, National Centre for Scientific Research "Demokritos"; ⁴ Unit of Biomedical Applications, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece; ⁵ Clinical Cytogenetics Laboratory, University of Columbia Medical Center, New York, New York; ⁶ Departments of General Biology and Pharmacology, School of Medicine, University of Patras, Patras, Greece; ⁷ Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark; and ⁸ Department of Molecular Biology, University of Geneva, Geneva, Switzerland

Requests for reprints: Vassilis G. Gorgoulis, Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Antaiou 53 Str., Lamprini, Ano Patissia, GR-11146 Athens, Greece. Phone: 30-210-6535894; Fax. 30-210-6535894; E-mail: histoclub{at}ath.forthnet.gr or vgorg{at}med.uoa.gr.

The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients. Abnormal accumulation of both proteins occurred early from the stage of dysplasia. A frequent cause of unregulated hCdc6 and hCdt1 expression was gene amplification, suggesting that these components can play a role per se in cancer development. Overexpression of hCdt1 and hCdc6 promoted rereplication and generated a DNA damage response, which activated the antitumor barriers of senescence and apoptosis. Generating an inducible hCdt1 cellular system, we observed that continuous stimulus by deregulated hCdt1 led to abrogation of the antitumor barriers and resulted in the selection of clones with more aggressive properties. In addition, stable expression of hCdc6 and hCdt1 in premalignant papilloma cells led to transformation of the cells that produced tumors upon injection into nude mice depicting the oncogenic potential of their deregulation. [Cancer Res 2007;67(22):10899–909]

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