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1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 2 Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 3 Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA; 4 Department of Ophthalmology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA; 5 Department of Biochemistry, University of Washington, Seattle, Washington 98109, USA
The cell cycle inhibitor p27Kip1 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 (p27CK–). In striking contrast to complete deletion of the cdkn1b gene, which causes spontaneous tumorigenesis only in the pituitary, the p27CK– 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, p27Kip1 promoted stem cell expansion and functioned as a dominant oncogene in vivo. Thus, the p27CK– 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 p27CK– 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: p27Kip1; lung tumor; oncogene; retina; bronchioalveolar stem cell; desquamative interstitial pneumonitis]
Received March 30, 2007; revised version accepted May 31, 2007.
E-MAIL jroberts{at}fhcrc.org; FAX (206) 667-6877.
Supplemental material is available at http://www.genesdev.org.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1556607
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Genes & Dev. 2007 21: 1703-1706.
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