title: Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
abstract: 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.
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Michalis
authors.initials: M
authors.lastname: Liontos
authors.forename: Marilena
authors.initials: M
authors.lastname: Koutsami
authors.forename: Maria
authors.initials: M
authors.lastname: Sideridou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Evangelou
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.forename: Brynn
authors.initials: B
authors.lastname: Levy
authors.forename: Athanassios
authors.initials: A
authors.lastname: Kotsinas
authors.forename: Odelia
authors.initials: O
authors.lastname: Nahum
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zoumpourlis
authors.forename: Mirsini
authors.initials: M
authors.lastname: Kouloukoussa
authors.forename: Zoi
authors.initials: Z
authors.lastname: Lygerou
authors.forename: Stavros
authors.initials: S
authors.lastname: Taraviras
authors.forename: Christos
authors.initials: C
authors.lastname: Kittas
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000502:physiology; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents; C103706:CDC6 protein, human; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins