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Molecular and Cellular Biology, December 2008, p. 7442-7450, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00138-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cdc25A Serine 123 Phosphorylation Couples Centrosome Duplication with DNA Replication and Regulates Tumorigenesis{triangledown} ,{dagger}

Sathyavageeswaran Shreeram, Weng Kee Hee, and Dmitry V. Bulavin*

Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore

Received 24 January 2008/ Returned for modification 26 March 2008/ Accepted 1 October 2008

The cell division cycle 25A (Cdc25A) phosphatase is a critical regulator of cell cycle progression under normal conditions and after stress. Stress-induced degradation of Cdc25A has been proposed as a major way of delaying cell cycle progression. In vitro studies pointed toward serine 123 as a key site in regulation of Cdc25A stability after exposure to ionizing radiation (IR). To address the role of this phosphorylation site in vivo, we generated a knock-in mouse in which alanine was substituted for serine 123. The Cdc25 S123A knock-in mice appeared normal, and, unexpectedly, cells derived from them exhibited unperturbed cell cycle and DNA damage responses. In turn, we found that Cdc25A was present in centrosomes and that Cdc25A levels were not reduced after IR in knock-in cells. This resulted in centrosome amplification due to lack of induction of Cdk2 inhibitory phosphorylation after IR specifically in centrosomes. Further, Cdc25A knock-in animals appeared sensitive to IR-induced carcinogenesis. Our findings indicate that Cdc25A S123 phosphorylation is crucial for coupling centrosome duplication to DNA replication cycles after DNA damage and therefore is likely to play a role in the regulation of tumorigenesis.

* Corresponding author. Mailing address: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore. Phone: 65 6586 9589. Fax: 65 6779 1117. E-mail: dvbulavin{at}imcb.a-star.edu.sg

{triangledown} Published ahead of print on 20 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2008, p. 7442-7450, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00138-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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