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  • Original Article
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Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro

Abstract

p27Kip1 (p27) can have opposing roles during malignant transformation depending on cellular context: on one hand it functions as a tumor suppressor by inhibiting cyclin–cyclin-dependent kinase (CDK) activity in the nucleus and on the other it may adopt an oncogenic role that is less well understood. To gain further insight into the roles played by p27 during tumorigenesis, we compared the susceptibility with urethane-induced tumorigenesis of two p27 mouse models, p27−/− and p27CK− knockin, in which p27 cannot bind or inhibit cyclin–CDKs. In this K-Ras-driven tumorigenesis model, p27CK− mice had an increase in both tumor number and aggressiveness compared with p27−/−, indicating a cooperation between p27CK− and activated Ras. In the lung, increased tumorigenesis was associated with cytoplasmic localization of p27CK− and bronchiolaveolar stem cell amplification. The ability of p27CK− to cooperate with other oncogenes was not universal. When c-Myc was used as a transforming agent, p27 status became irrelevant and c-Myc was equally potent in transforming p27+/+, p27−/− and p27CK− cells. In fact, c-Myc induced the degradation of wild-type p27 via the Skp-Cullin-F-box (SCF)–Skp2 pathway. In contrast, p27CK− levels were not affected by c-Myc expression, as p27CK− is insensitive to Skp2-mediated degradation because of its inability to bind cyclin E/CDK2. However, in presence of c-Myc, p27CK− remained mostly nuclear, providing an explanation for its inability to cooperate with Myc during transformation. Thus, we propose that the p27CK− protein needs to be localized in the cytoplasm in order to function as an oncogene, otherwise it just behaves similar to a null allele.

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Acknowledgements

MPS is supported by a studentship from the Ministère de l’Enseignement Supérieur et de la Recherche. CC is supported by a fellowship from the Fondation pour la Recherche Médicale. This work was supported by NIH grant #1R01CA118043 to JMR. AB is supported by grants from the Association pour la Recherche sur le Cancer and Ligue Nationale Contre le Cancer.

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Correspondence to A Besson.

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Serres, M., Zlotek-Zlotkiewicz, E., Concha, C. et al. Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro. Oncogene 30, 2846–2858 (2011). https://doi.org/10.1038/onc.2011.9

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