Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1).
p27(Kip1) and p21(Cip1) are thought to suppress tumor growth and prevent cell cycle progression by inhibiting Cdk2-cyclin E/A kinases. Since Cdk2 is dispensable for mitotic cell division, we analyzed the activity of these inhibitors in Cdk2-deficient cells. Ectopic expression of p27(Kip1) or p21(Cip1) efficiently inhibits cell cycle progression of Cdk2(-/-) fibroblasts. Loss of p27(Kip1) or p21(Cip1) confers similar proliferative advantages to Cdk2(+/+) and Cdk2(-/-) cells. Moreover, Cdk2 is dispensable for p21(Cip1)-induced cell cycle arrest after DNA damage. Finally, ablation of Cdk2 in p27(Kip1) null mice does not suppress their phenotypic defects, including development of pituitary tumors. These results indicate that Cdk2 is not an essential target for p27(Kip1) and p21(Cip1) in cell cycle inhibition and tumor suppression.
Martín
Alberto
A
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
Odajima
Junko
J
Hunt
Sarah L
SL
Dubus
Pierre
P
Ortega
Sagrario
S
Malumbres
Marcos
M
Barbacid
Mariano
M
D000818:Animals; D001835:Body Weight / Q000235:genetics; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology; D015792:Retinal Dysplasia / Q000235:genetics / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005047:Etoposide; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases