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First published online 11 September 2008
doi: 10.1242/dev.024919

Development 135, 3389-3400 (2008)
Published by The Company of Biologists 2008
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Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2

Ande Satyanarayana1, Cyril Berthet1,*, Javier Lopez-Molina2, Vincenzo Coppola1, Lino Tessarollo1 and Philipp Kaldis1,3,{dagger}

1 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Bldg. 560/22-56, 1050 Boyles Street, Frederick, MD 21702-1201, USA.
2 Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA.
3 Institute of Molecular and Cell Biology (IMCB), Proteos, 61 Biopolis Drive, 138673 Singapore.

{dagger} Author for correspondence (e-mail: kaldis{at}imcb.a-star.edu.sg)

Accepted 20 August 2008

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.

Key words: Cell cycle regulation, Cyclin, Cyclin-dependent kinase (Cdk), Meiosis, Mouse genetics


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Development 2008 135: e2003. [Full Text]  





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