Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype.
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.
Besson
Arnaud
A
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Hwang
Harry C
HC
Cicero
Samantha
S
Donovan
Stacy L
SL
Gurian-West
Mark
M
Johnson
Dianna
D
Clurman
Bruce E
BE
Dyer
Michael A
MA
Roberts
James M
JM
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001980:Bronchi / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D009857:Oncogenes; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000473:pathology; D019572:Retinal Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology
C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27