Duality of p27Kip1 function in tumorigenesis

In this issue of Genes & Development, Besson et al. (2007) report phenotypic characteristics of a novel knock-in mouse strain expressing a mutant allele of the cell cycle inhibitor p27 KiP1 that has both common and unique features when compared with a null allele. The new studies provide the first direct in vivo evidence that in addition to its role as a tumor suppressor, p27 Kip1 also functions as an oncogene. The work also suggests that p27 Kip1 oncogenic activity leads to aberrant stem and progenitor cell expansion in the lung and retina, respectively. Thus, p27 KiP1 's new dark side may serve an oncogenic function that operates in less specialized cell types to influence tumorigenesis. creased patient survival (Slingerland and Pagano 2000). Germline mutation of p27 Kip1 was also recently described in a subset of MEN (Multiple Endocrine Neoplasia) syndrome patients in humans, as well as in rats with the related MENX syndrome (Pellegata et al. 2006). p27 Kip1 -null mice develop organomegaly and pituitary adenomas (Fero et al. 1996; Kiyokawa et al. 1996; Nakayama et al. 1996). The most simplistic explanation of the phenotypes was that in p27 Kip1-/- mice, the deregulated CDK2 kinase was responsible for these symptoms. However, recent observations that ablation of CDK2 in p27 Kip1 -null background did not mitigate the phenotypes of p27 Kip1 deficiency clearly shows that p27 Kip1 can act independently of CDK2, likely in part by hyperactivating CDK1 (Aleem et al. 2005; Martin et al. 2005).