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Molecular and Cellular Biology, April 2005, p. 3364-3387, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3364-3387.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphorylation of p21 in G₂/M Promotes Cyclin B-Cdc2 Kinase Activity

Bipin C. Dash and Wafik S. El-Deiry^*

Laboratory of Molecular Oncology and Cell Cycle Regulation, Departments of Medicine, Genetics, and Pharmacology, and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Received 14 July 2004/ Returned for modification 9 September 2004/ Accepted 3 January 2005

Little is known about the posttranslational control of the cyclin-dependent protein kinase (CDK) inhibitor p21. We describe here a transient phosphorylation of p21 in the G₂/M phase. G₂/M-phosphorylated p21 is short-lived relative to hypophosphorylated p21. p21 becomes nuclear during S phase, prior to its phosphorylation by CDK2. S126-phosphorylated cyclin B1 binds to T57-phosphorylated p21. Cdc2 kinase activation is delayed in p21-deficient cells due to delayed association between Cdc2 and cyclin B1. Cyclin B1-Cdc2 kinase activity and G₂/M progression in p21^–/– cells are restored after reexpression of wild-type but not T57A mutant p21. The cyclin B1 S126A mutant exhibits reduced Cdc2 binding and has low kinase activity. Phosphorylated p21 binds to cyclin B1 when Cdc2 is phosphorylated on Y15 and associates poorly with the complex. Dephosphorylation on Y15 and phosphorylation on T161 promotes Cdc2 binding to the p21-cyclin B1 complex, which becomes activated as a kinase. Thus, hyperphosphorylated p21 activates the Cdc2 kinase in the G₂/M transition.

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* Corresponding author. Mailing address: University of Pennsylvania, 415 Curie Blvd., CRB 437A, Philadelphia, PA 19104. Phone: (215) 898-9015. Fax: (215) 573-9139. E-mail: wafik{at}mail.med.upenn.edu.

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

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Molecular and Cellular Biology, April 2005, p. 3364-3387, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3364-3387.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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