Abstract
The cyclin-dependent kinase inhibitor p27(Kip1) is known as a negative regulator of cell-cycle progression and as a tumour suppressor. Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27(-/-) mouse phenotype. Here, we show that although p27(-/-) Cdk2(-/-) mice developed ovary tumours and tumours in the anterior lobe of the pituitary, we failed to detect any functional complementation in p27(-/-) Cdk2(-/-) double-knockout mice, indicating a parallel pathway regulated by p27. We observed elevated levels of S phase and mitosis in tissues of p27(-/-) Cdk2(-/-) mice concomitantly with elevated Cdc2 activity in p27(-/-) Cdk2(-/-) extracts. p27 binds to Cdc2, cyclin B1, cyclin A2, or suc1 complexes in wild-type and Cdk2(-/-) extracts. In addition, cyclin E binds to and activates Cdc2. Our in vivo results provide strong evidence that Cdc2 may compensate the loss of Cdk2 function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2-Aminopurine / analogs & derivatives
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2-Aminopurine / pharmacology
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Animals
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Body Weight / genetics
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism*
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CDC2-CDC28 Kinases / genetics
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CDC2-CDC28 Kinases / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Proliferation
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Crosses, Genetic
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Cyclin E / metabolism*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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Cyclins / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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G1 Phase / genetics
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G1 Phase / physiology*
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Gonads / pathology
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Infertility / genetics
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Interphase / drug effects
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Interphase / genetics
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Interphase / physiology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitosis / genetics
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Pituitary Neoplasms / genetics
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Pituitary Neoplasms / pathology
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Protein Binding
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RNA, Double-Stranded / genetics
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S Phase / drug effects
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S Phase / genetics
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S Phase / physiology*
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Sex Factors
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Spleen / metabolism
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Thymus Gland / metabolism
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Thymus Gland / pathology
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin E
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Cyclins
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Enzyme Inhibitors
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N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine
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RNA, Double-Stranded
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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2-Aminopurine
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CDC2 Protein Kinase
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CDC2-CDC28 Kinases
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Cdk2 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases