Abstract
Cyclin E and p27Kip1 are key regulators for cyclin-dependent kinases (Cdks) acting at the G1-/S-phase transition of the cell cycle. Whereas cyclin E is required for the activation of Cdk2, p27Kip1 is a specific Cdk inhibitor and can block cell division. High levels of cyclin E and low levels of p27Kip1 expression have been associated with malignant lymphomas in humans; the level of p27Kip1 is even considered of prognostic significance. However, mice that lack p27Kip1 do not develop any malignant lymphomas despite a pronounced lymphoid hyperplasia in thymus and spleen. We have previously described transgenic mice that carry a construct in which the cyclin E cDNA is under the control of the CD2 promoter/enhancer region and thus express high levels of cyclin E in the T-cell compartment (CD2-cyclin E). These animals are not predisposed for T-cell lymphomas in the absence of other cooperating events. Here we show that T-cells from CD2-cyclin E mice that at the same time are deficient for p27Kip1 show a significantly higher Cdk2 activity than cells from wilde-type or single mutant animals. Accordingly, a higher percentage of T cells in S/G2/M phase is found in CD2-cyclin E/p27Kip1−/− mice. After a long latency period of over 200 days, these animals develop spontaneous monoclonal T cell lymphoma whereas none of the single CD2-cyclin E transgenics or the p27Kip1-deficient mice showed any sign of lymphoid malignancies. Our findings demonstrate that a deregulation of control mechanisms at the G1/S transition by the combination of high cyclin E levels in the absence of p27Kip1 is sufficient to predispose mice to develop lymphoid malignancies and further support a role of p27Kip1 as a tumor suppressor and of cyclin E as a dominant oncogene.
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Acknowledgements
This work was supported by grants of the Deutsche Forschungsgemeinschaft (Mo 435/11-1) and the Dr Mildred Scheel Stiftung für Krebsforschung and the Fonds der chemischen Industrie.
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Geisen, C., Karsunky, H., Yücel, R. et al. Loss of p27Kip1 cooperates with cyclin E in T-cell lymphomagenesis. Oncogene 22, 1724–1729 (2003). https://doi.org/10.1038/sj.onc.1206340
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DOI: https://doi.org/10.1038/sj.onc.1206340
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