Abstract
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.
