Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Abstract

The cell cycle inhibitor p27 Kip1 also has cyclin-cyclin-dependent kinase (CDK)-independent functions. To investigate the significance of these functions in vivo, we generated a knock-in mouse in which four amino acid substitutions in the cdkn1b gene product prevent its interaction with cyclins and CDKs (p27 CK − ). In striking contrast to complete deletion of the cdkn1b gene, which causes spontaneous tumorigenesis only in the pituitary, the p27 CK − protein dominantly caused hyperplastic lesions and tumors in multiple organs, including the lung, retina, pituitary, ovary, adrenals, spleen, and lymphomas. Moreover, the high incidence of spontaneous tumors in the lung and retina was associated with amplification of stem/progenitor cell populations. Therefore, independently of its role as a CDK inhibitor, p27 Kip1 promoted stem cell expansion and functioned as a dominant oncogene in vivo. Thus, the p27 CK − mouse unveils a dual role for p27 during tumorigenesis: It is a tumor suppressor by virtue of its cyclin-CDK regulatory function, and also an oncogene through a cyclin-CDK-independent function. This may explain why the cdkn1b gene is rarely inactivated in human tumors, and the p27 CK − mouse in which the tumor suppressor function is lost but the cyclin-CDK-independent-oncogenic-function is maintained may represent a more faithful model for the widespread role of p27 misregulation in human cancers than the p27 null.[Keywords: p27 Kip1 ; lung tumor; oncogene; retina; bronchioalveolar stem cell; desquamative interstitial pneumonitis] Supplemental material is available at http://www.genesdev.org.

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

“…Thus, P27 kip1 deregulation induced by GGTI treatment may modify the G1 phase of the cell cycle, disturb breast CSC self-renewal, and induce differentiation. In support of this hypothesis, knockin mice in which the P27 protein is unable to interact with cyclins and CDKs developed tumors in multiple organs and this high incidence of spontaneous tumors was associated with amplification of stem/progenitor cell populations [42].…”

Combined loss of p21waf1/cip1 and p27kip1 enhances tumorigenesis in mice

“…14,[28][29][30][31] In addition, CDK-independent functions have been described for p21 and p27, highlighting their role as oncogenes or in cellular stress in different tissues, implicating p21 and p27 as possible therapeutic targets in some processes. 32,33 Up to now, no studies have been described using a doublenull murine model for p21 and p27. Thus, the main aim of our work is to study the possible oncogenic cooperation of both CDKIs, analyzing the susceptibility to spontaneous tumorigenesis in a double-null murine model generated in our laboratory.…”

Un nouveau rôle de p27KIP1dans la mitose ?

“…Par conséquent, p27 semble impliquée dans les phases finales de la cytocinèse via la régulation de l'activation de citron-K par les protéines Rho. Ces résultats fournissent un mécanisme potentiel qui pourrait expliquer la susceptibilité accrue des souris p27 CK-à la tumorigenèse [4]. Chez l'homme, des études cliniques associent la localisation cytoplasmique de p27 avec des tumeurs agressives de haut grade et la présence de métastases [1].…”