p27 Kip1 (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 p27 CK− knockin, in which p27 cannot bind or inhibit cyclin–CDKs. In this K-Ras-driven tumorigenesis model, p27 CK− mice had an increase in both tumor number and aggressiveness compared with p27−/−, indicating a cooperation between p27 CK− and activated Ras. In the lung, increased tumorigenesis was associated with cytoplasmic localization of p27 CK− and bronchiolaveolar stem cell amplification. The ability of p27 CK− 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 p27 CK− cells. In fact, c-Myc induced the degradation of wild-type p27 via the Skp-Cullin-F-box (SCF)–Skp2 pathway. In contrast, p27 CK− levels were not affected by c-Myc expression, as p27 CK− is insensitive to Skp2-mediated degradation because of its inability to bind cyclin E/CDK2. However, in presence of c-Myc, p27 CK− remained mostly nuclear, providing an explanation for its inability to cooperate with Myc during transformation. Thus, we propose that the p27 CK− protein needs to be localized in the cytoplasm in order to function as an oncogene, otherwise it just behaves similar to a null allele.