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Molecular and Cellular Biology, August 2004, p. 6653-6664, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6653-6664.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Genetic Evidence for Functional Dependency of p18^Ink4c on Cdk4

Lineberger Comprehensive Cancer Center,¹ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,³ Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, Illinois 60607²

Received 3 March 2004/ Returned for modification 9 April 2004/ Accepted 10 May 2004

The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and induces the growth-suppressive function of Rb family proteins. Mutations in the Cdk4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice, suggesting that INK4 is a major regulator of CDK4. Mice lacking the Cdk4 gene exhibit various defects in many organs associated with hypocellularity, whereas loss of the p18^Ink4c gene results in widespread hyperplasia and organomegaly. To genetically test the notion that the function of INK4 is dependent on CDK4, we generated p18; Cdk4 double-mutant mice and examined the organs and tissues which developed abnormalities when either gene is deleted. We show here that, in all organs we have examined, including pituitary, testis, pancreas, kidney, and adrenal gland, hyperproliferative phenotypes associated with p18 loss were canceled. The double-mutant mice exhibited phenotypes very close to or indistinguishable from that of Cdk4 single-mutant mice. Mice lacking p27^Kip1 develop widespread hyperplasia and organomegaly similar to those developed by p18-deficient mice. The p27; Cdk4 double-mutant mice, however, displayed phenotypes intermediate between those of p27 and Cdk4 single-mutant mice. These results provide genetic evidence that in mice p18^Ink4c and p27^Kip1 mediate the transduction of different cell growth and proliferation signals to CDK4 and that p18^Ink4c is functionally dependent on CDK4.

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