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Molecular and Cellular Biology, August 2003, p. 5556-5571, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5556-5571.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Silencing of the Novel p53 Target Gene Snk/Plk2 Leads to Mitotic Catastrophe in Paclitaxel (Taxol)-Exposed Cells

Timothy F. Burns, Peiwen Fei, Kimberly A. Scata, David T. Dicker, and Wafik S. El-Deiry*

Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Genetics, and Pharmacology and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Received 11 February 2003/ Returned for modification 14 March 2003/ Accepted 22 May 2003

Loss of p53 sensitizes to antimicrotubule agents in human tumor cells, but little is known about its role during mitosis. We have identified the Polo-like kinase family member serum inducible kinase (Snk/Plk2) as a novel p53 target gene. Snk/Plk2 mutagenesis demonstrated that its kinase activity is negatively regulated by its C terminus. Small interfering RNA (siRNA)-mediated Snk/Plk2 silencing in the presence of the mitotic poisons paclitaxel (Taxol) or nocodazole significantly increased apoptosis, similar to p53 mutations, which confer paclitaxel sensitivity. Furthermore, we have demonstrated that the apoptosis due to silencing of Snk/Plk2 in the face of spindle damage occurs in mitotic cells and not in cells that have progressed to a G1-like state without dividing. Since siRNA directed against Snk/Plk2 promoted death of paclitaxel-treated cells in mitosis, we envision a mitotic checkpoint wherein p53-dependent activation of Snk/Plk2 prevents mitotic catastrophe following spindle damage. Finally, these studies suggest that disruption of Snk/Plk2 may be of therapeutic value in sensitizing paclitaxel-resistant tumors.

* Corresponding author. Mailing address: HHMI, 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.

Molecular and Cellular Biology, August 2003, p. 5556-5571, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5556-5571.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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