Abstract
In the absence of mitogenic stimuli, cells normally arrest in G1/0, because they fail to pass the G1-restriction point. However, abrogation of the G1-restriction point (by loss of the retinoblastoma gene family) reveals a second-restriction point that arrests cells in G2. Serum-starvation-induced G2 arrest is effectuated through inhibitory interactions of p27KIP1 and p21CIP1 with cyclins A and B1 and can be reversed through mitogen re-addition. In this study, we have investigated the pathways that allow cell cycle re-entry from this G2 arrest. We provide evidence that recovery from G2 arrest depends on the rat sarcoma viral oncogene (RAS) and phosphatidylinositol-3 kinase pathways and show that oncogenic hits, such as overexpression of c-MYC or mutational activation of RAS can abrogate the G2-restriction point. Together, our results provide new mechanistic insight into multistep carcinogenesis.
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Acknowledgements
We thank Rob Wolthuis, Marieke Aarts and Tinke Vormer for fruitful discussions and for critically reading the manuscript. We are grateful to the Dutch Cancer Society for financial support (Grants NKI 2000-2232 and NKI 2002-2634). FF is a recipient of a Dutch Cancer Society Postdoctoral fellowship.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Foijer, F., Simonis, M., van Vliet, M. et al. Oncogenic pathways impinging on the G2-restriction point. Oncogene 27, 1142–1154 (2008). https://doi.org/10.1038/sj.onc.1210724
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DOI: https://doi.org/10.1038/sj.onc.1210724
