期刊
GENES & DEVELOPMENT
卷 21, 期 14, 页码 1731-1746出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1556607
关键词
p27(Kip1); lung tumor; oncogene; retina; bronchioalveolar stem cell; desquamative interstitial pneumonitis
资金
- NCI NIH HHS [R01 CA118043, 1R01CA118043] Funding Source: Medline
- NHLBI NIH HHS [1K08HL073670-01, K08 HL073670] Funding Source: Medline
- PHS HHS [R01084069] Funding Source: Medline
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.
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