Genetic evidence for functional dependency of p18Ink4c on Cdk4

Xin-Hai Pei, Feng Bai, Tateki Tsutsui, Hiroaki Kiyokawa, Yue Xiong

Research output: Contribution to journalArticle

34 Citations (Scopus)

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 p18Ink4c 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 p27Kip1 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 p18Ink4c and p27 Kip1 mediate the transduction of different cell growth and proliferation signals to CDK4 and that p18Ink4c is functionally dependent on CDK4.

Original languageEnglish
Pages (from-to)6653-6664
Number of pages12
JournalMolecular and Cellular Biology
Volume24
Issue number15
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

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Phenotype
Genes
Hyperplasia
Cyclin-Dependent Kinase Inhibitor Proteins
Cyclin D
Retinoblastoma Protein
Adrenal Glands
Growth
Testis
Pancreas
Cell Proliferation
Kidney
Mutation
Neoplasms
Cutaneous Malignant Melanoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Genetic evidence for functional dependency of p18Ink4c on Cdk4. / Pei, Xin-Hai; Bai, Feng; Tsutsui, Tateki; Kiyokawa, Hiroaki; Xiong, Yue.

In: Molecular and Cellular Biology, Vol. 24, No. 15, 01.08.2004, p. 6653-6664.

Research output: Contribution to journalArticle

Pei, Xin-Hai ; Bai, Feng ; Tsutsui, Tateki ; Kiyokawa, Hiroaki ; Xiong, Yue. / Genetic evidence for functional dependency of p18Ink4c on Cdk4. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 15. pp. 6653-6664.
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