Cdc2-cyclin E complexes regulate the G1/S phase transition.
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.
Aleem
Eiman
E
Mouse Cancer Genetics Program, National Cancer Institute, NCI-Frederick, Bldg 560/22-56, 1050 Boyles Street, Frederick, MD 21702-1201, USA.
Kiyokawa
Hiroaki
H
Kaldis
Philipp
P
D015075:2-Aminopurine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics / Q000502:physiology*; D006066:Gonads / Q000473:pathology; D007246:Infertility / Q000235:genetics; D007399:Interphase / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D012330:RNA, Double-Stranded / Q000235:genetics; D016196:S Phase / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012737:Sex Factors; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019927:Cyclin E; D016213:Cyclins; D004791:Enzyme Inhibitors; C469937:N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine; D012330:RNA, Double-Stranded; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015075:2-Aminopurine; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases