Authors: Xouri, Georgia¹; Lygerou, Zoi¹; Nishitani, Hideo²; Pachnis, Vassilis³; Nurse, Paul; Taraviras, Stavros⁴

Source: FEBS Journal, Volume 271, Number 16, August 2004 , pp. 3368-3378(11)

Publisher: Wiley-Blackwell

Abstract:

Licensing origins for replication upon completion of mitosis ensures genomic stability in cycling cells. Cdt1 was recently discovered as an essential licensing factor, which is inhibited by geminin. Over-expression of Cdt1 was shown to predispose cells for malignant transformation. We show here that Cdt1 is down-regulated at both the protein and RNA level when primary human fibroblasts exit the cell cycle into G0, and its expression is induced as cells re-enter the cell cycle, prior to S phase onset. Cdt1's inhibitor, geminin, is similarly down-regulated upon cell cycle exit at both the protein and RNA level, and geminin protein accumulates with a 3-6 h delay over Cdt1, following serum re-addition. Similarly, mouse NIH3T3 cells down-regulate Cdt1 and geminin mRNA and protein when serum starved. Our data suggest a transcriptional control over Cdt1 and geminin at the transition from quiescence to proliferation. In situ hybridization and immunohistochemistry localize Cdt1 as well as geminin to the proliferative compartment of the developing mouse gut epithelium. Cdt1 and geminin levels were compared in primary cells vs. cancer-derived human cell lines. We show that Cdt1 is consistently over-expressed in cancer cell lines at both the protein and RNA level, and that the Cdt1 protein accumulates to higher levels in individual cancer cells. Geminin is similarly over-expressed in the majority of cancer cell lines tested. The relative ratios of Cdt1 and geminin differ significantly amongst cell lines. Our data establish that Cdt1 and geminin are regulated at cell cycle exit, and suggest that the mechanisms controlling Cdt1 and geminin levels may be altered in cancer cells.

Keywords: cancer; Cdt1; G0; geminin; licensing

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1432-1033.2004.04271.x

Affiliations: 1: Laboratory of General Biology, Medical School, University of Patras, Rio, Patras, Greece 2: Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan 3: Division of Molecular Neurobiology, National Institute for Medical Research, London, UK 4: Laboratory of Pharmacology, Medical School, University of Patras, Rio, Patras, Greece

Publication date: 2004-08-01

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