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Molecular and Cellular Biology, March 2003, p. 2171-2181, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.2171-2181.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Stabilization of p53 by CP-31398 Inhibits Ubiquitination without Altering Phosphorylation at Serine 15 or 20 or MDM2 Binding

Wenge Wang,1 Rishu Takimoto,1 Farzan Rastinejad,2 and Wafik S. El-Deiry1*

Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Genetics, Pharmacology, and Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,1 Cancer Drug Discovery, Pfizer Global Research and Development, Groton, Connecticut 063402

Received 19 July 2002/ Returned for modification 4 September 2002/ Accepted 13 December 2002

CP-31398, a styrylquinazoline, emerged from a high throughput screen for therapeutic agents that restore a wild-type-associated epitope (monoclonal antibody 1620) on the DNA-binding domain of the p53 protein. We found that CP-31398 can not only restore p53 function in mutant p53-expressing cells but also significantly increase the protein level and promote the activity of wild-type p53 in multiple human cell lines, including ATM-null cells. Cells treated with CP-31398 undergo either cell cycle arrest or apoptosis. Further investigation showed that CP-31398 blocks the ubiquitination and degradation of p53 but not in human papillomavirus E6-expressing cells. Of note, CP-31398 does not block the physical association between p53 and MDM2 in vivo. Moreover, unlike the DNA-damaging agent adriamycin, which induces strong phosphorylation of p53 on serines 15 and 20, CP-31398 exposure leads to no measurable phosphorylation on these sites. We found that CP-31398 could also stabilize exogenous p53 in p53 mutant, wild-type, and p53-null human cells, even in MDM2-null p53-/- mouse embryonic fibroblasts. Our results suggest a model wherein CP-31398-mediated stabilization of p53 may result from reduced ubiquitination, leading to high levels of transcriptionally active p53. Further understanding of this mechanism may lead to novel strategies for p53 stabilization and tumor suppression in cancers, even those with absent ARF or high MDM2 expression.

* Corresponding author. Mailing address: Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437, Philadelphia, PA 19104. Phone: (215) 898-9015. Fax: (215) 573-9139. E-mail: wafik{at}mail.med.upenn.edu.

Molecular and Cellular Biology, March 2003, p. 2171-2181, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.2171-2181.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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