Cdk1 is sufficient to drive the mammalian cell cycle.
Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.
Santamaría
David
D
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain.
Barrière
Cédric
C
Cerqueira
Antonio
A
Hunt
Sarah
S
Tardy
Claudine
C
Newton
Kathryn
K
Cáceres
Javier F
JF
Dubus
Pierre
P
Malumbres
Marcos
M
Barbacid
Mariano
M
D000818:Animals; D016203:CDC2 Protein Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology* / Q000196:embryology / Q000201:enzymology* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D020043:Genes, Essential / Q000235:genetics; D007399:Interphase; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D038081:Organogenesis
D016213:Cyclins; D008934:Mitogens; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases