Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
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.
Liontos
Michalis
M
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
Koutsami
Marilena
M
Sideridou
Maria
M
Evangelou
Konstantinos
K
Kletsas
Dimitris
D
Levy
Brynn
B
Kotsinas
Athanassios
A
Nahum
Odelia
O
Zoumpourlis
Vassilis
V
Kouloukoussa
Mirsini
M
Lygerou
Zoi
Z
Taraviras
Stavros
S
Kittas
Christos
C
Bartkova
Jirina
J
Papavassiliou
Athanasios G
AG
Bartek
Jiri
J
Halazonetis
Thanos D
TD
Gorgoulis
Vassilis G
VG
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
D000970:Antineoplastic Agents; C103706:CDC6 protein, human; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins