Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2.
It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1Cdk2KI). Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus. In addition, we generated Cdk2-/- Cdk1+/Cdk2KI mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. We found that both male and female Cdk2-/- Cdk1+/Cdk2KI mice were sterile, similar to Cdk2-/- mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. The translocational and cell cycle properties of knockin Cdk2 in Cdk2-/- Cdk1+/Cdk2KI cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1 during liver regeneration in the absence of Cdk2. This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo.
Satyanarayana
Ande
A
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Bldg. 560/22-56, 1050 Boyles Street, Frederick, MD 21702-1201, USA.
Berthet
Cyril
C
Lopez-Molina
Javier
J
Coppola
Vincenzo
V
Tessarollo
Lino
L
Kaldis
Philipp
P
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005804:Genes, Lethal; D007150:Immunohistochemistry; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice
D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2
Cell. 1999 Jun 11;97(6):767-77
10380928
Curr Biol. 2003 Oct 14;13(20):1775-85
14561402
Dev Biol. 1999 Mar 15;207(2):408-18
10068472
Mol Cell Biol. 2005 Feb;25(3):1081-8
15657434
Nat Genet. 2003 Sep;35(1):25-31
12923533
J Biol Chem. 1993 Sep 25;268(27):20443-51
8397207
Dev Cell. 2006 May;10(5):563-73
16678773
Nat Cell Biol. 2005 Aug;7(8):831-6
16007079
Cell Cycle. 2004 Nov;3(11):1405-17
15492508
Curr Opin Genet Dev. 1998 Feb;8(1):21-7
9529601
Cell. 1988 Jul 29;54(3):423-31
3293802
J Cell Biol. 1999 Jan 25;144(2):213-24
9922449
Genes Dev. 1997 Jun 1;11(11):1464-78
9192873
Cell. 1989 May 5;57(3):393-401
2541912
EMBO J. 1989 Dec 20;8(13):3985-95
2686978
Cell. 1995 May 5;81(3):323-30
7736585
Genomics. 2001 Apr 1;73(1):56-65
11352566
Cell. 2004 Sep 3;118(5):535-8
15339658
Genome Res. 2003 Mar;13(3):476-84
12618378
EMBO Rep. 2005 May;6(5):432-7
15864294
Curr Opin Cell Biol. 1993 Apr;5(2):166-79
8507488
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2907-11
1372993
J Hepatol. 2000;32(1 Suppl):19-31
10728791
J Cell Sci. 1992 Mar;101 ( Pt 3):529-45
1387877
Hepatogastroenterology. 2001 Mar-Apr;48(38):556-62
11379353
EMBO J. 2003 Aug 1;22(15):4003-13
12881434
Results Probl Cell Differ. 2006;42:271-328
16903215
J Cell Biol. 1991 Oct;115(1):1-17
1717476
Mol Biol Cell. 1993 Dec;4(12):1337-50
7513216
Cell. 2004 Aug 20;118(4):493-504
15315761
Annu Rev Cell Dev Biol. 1997;13:261-91
9442875
Mol Cell Biol. 1982 Apr;2(4):412-25
6287237
Mol Biol Cell. 2008 Jan;19(1):65-77
17942597
Nature. 2007 Aug 16;448(7155):811-5
17700700