Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division1. 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 mitosis2. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks3,4,5,6,7,8. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks8,9,10. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins11,12,13,14. 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.
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This work is dedicated to the memory of our colleagues L. Gómez García and J. López Navarro. We thank R. González, M. San Román, B. Velasco and R. Villar for technical assistance, A. García for help with the cytometer, and A. Swat and S. Mouron for advice on quantitative RT–PCR. We also value the support provided by the Transgenic and Comparative Pathology Units of the CNIO. We thank M. Puyol for the Cdk2 and Cdk6 antibodies. This work was supported by grants from the Plan Nacional de Investigación Científica (D.S., M.M. and M.B.), the OncoCycle programme from the Comunidad de Madrid (M.M. and M.B.), Fondo de Investigación Sanitaria (D.S.), V Framework Programme of the European Union (M.B.) and INSERM and Association pour la Recherche contre le Cancer (P.D.). C.T., C.B. and A.C. were supported by fellowships from FEBS, la Ligue contre le Cancer (Comité de la Dordogne) and FPI (Ministerio de Educación y Ciencia), respectively.
Author Contributions M.B. supervised the entire project. M.B., D.S. and M.M. conceived and designed the experiments, and wrote the manuscript with comments from co-authors. C.B. generated the mouse strains and carried out most cell culture experiments and part of the protein analysis. A.C. was responsible for most protein analysis and part of the cell culture experiments. S.H. and C.T. characterized Cdc2a mutant mice. P.D. was responsible for histopathological analysis. J.F.C. and K.N. generated one of the Cdc2a mutant embryonic stem cell clones.
This file contains Supplementary Figures S1-S3 with Legends and Supplementary Table S1.
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Cell & Bioscience (2018)