Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Cyclin-dependent kinase 1 (Cdk1) is an archetypical kinase and a central regulator that drives cells through G2 phase and mitosis. Knockouts of Cdk2, Cdk3, Cdk4, or Cdk6 have resulted in viable mice, but the in vivo functions of Cdk1 have not been fully explored in mammals. Here we have generated a conditional-knockout mouse model to study the functions of Cdk1 in vivo. Ablation of Cdk1 leads to arrest of embryonic development around the blastocyst stage. Interestingly, liver-specific deletion of Cdk1 is well tolerated, and liver regeneration after partial hepatectomy is not impaired, indicating that regeneration can be driven by cell growth without cell division. The loss of Cdk1 does not affect S phase progression but results in DNA re-replication because of an increase in Cdk2/cyclin A2 activity. Unlike other Cdks, loss of Cdk1 in the liver confers complete resistance against tumorigenesis induced by activated Ras and silencing of p53.

[1]  M. Tanudji,et al.  Unmasking the Redundancy Between Cdk1 and Cdk2 at G2 Phase in Human Cancer Cell Lines , 2006, Cell cycle.

[2]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[3]  P. Kaldis,et al.  Cdk2 and Cdk4 Activities Are Dispensable for Tumorigenesis Caused by the Loss of p53 , 2009, Molecular and Cellular Biology.

[4]  P. Kaldis,et al.  Cell-specific responses to loss of cyclin-dependent kinases , 2007, Oncogene.

[5]  David O. Morgan,et al.  The Cell Cycle: Principles of Control , 2014 .

[6]  C. Gilbert,et al.  Construction by gene targeting in human cells of a ‘conditional’ CDC2 mutant that rereplicates its DNA , 1997, Nature Genetics.

[7]  Pierre Dubus,et al.  Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1). , 2005, Cancer cell.

[8]  M. Barbacid,et al.  Cell cycle kinases in cancer. , 2007, Current opinion in genetics & development.

[9]  P. Kaldis,et al.  Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms , 2009, Oncogene.

[10]  M. DePamphilis,et al.  Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. , 2008, Genes & development.

[11]  J. Walter,et al.  Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. , 2007, Genes & development.

[12]  Jean S. Campbell,et al.  The role of hepatocytes and oval cells in liver regeneration and repopulation , 2003, Mechanisms of Development.

[13]  Corey M. Carlson,et al.  Somatic integration of an oncogene-harboring Sleeping Beauty transposon models liver tumor development in the mouse. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. Belur,et al.  Preferential delivery of the Sleeping Beauty transposon system to livers of mice by hydrodynamic injection , 2007, Nature Protocols.

[15]  Hongmao Sun,et al.  Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Labib.  How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? , 2010, Genes & development.

[17]  G. Hu,et al.  A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. , 2009, Cancer research.

[18]  P. Kaldis,et al.  Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2 , 2008, Development.

[19]  P. Pandolfi,et al.  Targeted Disruption of CDK4 Delays Cell Cycle Entry with Enhanced p27Kip1 Activity , 1999, Molecular and Cellular Biology.

[20]  P. Nurse,et al.  Involvement of p34cdc2 in establishing the dependency of S phase on mitosis , 1991, Nature.

[21]  J. Maller,et al.  Purification of maturation-promoting factor, an intracellular regulator of early mitotic events. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[22]  P. Thuriaux,et al.  Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. , 1980, Genetics.

[23]  D. Court,et al.  A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. , 2001, Genomics.

[24]  Pierre Dubus,et al.  Mammalian Cells Cycle without the D-Type Cyclin-Dependent Kinases Cdk4 and Cdk6 , 2004, Cell.

[25]  P. Kaldis,et al.  Cdk2 Knockout Mice Are Viable , 2003, Current Biology.

[26]  M. Magnuson,et al.  DNA excision in liver by an albumin‐Cre transgene occurs progressively with age , 2000, Genesis.

[27]  J. Harper,et al.  A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Kaldis,et al.  Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. , 2006, Developmental cell.

[29]  A. Evsikov,et al.  Cracking the egg: molecular dynamics and evolutionary aspects of the transition from the fully grown oocyte to embryo. , 2006, Genes & development.

[30]  Pierre Dubus,et al.  Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice , 2003, Nature Genetics.

[31]  P. Kaldis,et al.  p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint. , 2008, Molecular biology of the cell.

[32]  Clifford A. Meyer,et al.  Transcriptional role of cyclin D1 in development revealed by a genetic–proteomic screen , 2010, Nature.

[33]  Pierre Dubus,et al.  Cdk1 is sufficient to drive the mammalian cell cycle , 2007, Nature.

[34]  P. Kaldis,et al.  Cdc2–cyclin E complexes regulate the G1/S phase transition , 2005, Nature Cell Biology.