tailieunhanh - Báo cáo khoa học: 3 Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines

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 predis-pose 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. . | Eur. J. Biochem. 271 3368-3378 2004 FEBS 2004 doi Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines Georgia Xouri1. Zoi Lvaerou1. Hideo Nishitani2. Vassilis Pachnis3 Paul Nurse4 and Stavros Taraviras5 1Laboratory of General Biology Medical School University of Patras Rio Patras Greece 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 4Cell Cycle Laboratory Cancer Research UK London Laboratories London UK 5Laboratory of Pharmacology Medical School University of Patras Rio Patras Greece 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