title: Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro.
abstract: 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.
authors.affiliation: Cancer Research Center of Toulouse, France.
authors.forename: M P
authors.initials: MP
authors.lastname: Serres
authors.forename: E
authors.initials: E
authors.lastname: Zlotek-Zlotkiewicz
authors.forename: C
authors.initials: C
authors.lastname: Concha
authors.forename: M
authors.initials: M
authors.lastname: Gurian-West
authors.forename: V
authors.initials: V
authors.lastname: Daburon
authors.forename: J M
authors.initials: JM
authors.lastname: Roberts
authors.forename: A
authors.initials: A
authors.lastname: Besson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D014520:Urethane / Q000633:toxicity
chemical_list: D002273:Carcinogens; C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014520:Urethane