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Molecular and Cellular Biology, October 2003, p. 7096-7107, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7096-7107.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

14-3-3{sigma} Positively Regulates p53 and Suppresses Tumor Growth

Heng-Yin Yang,1 Yu-Ye Wen,1,2 Chih-Hsin Chen,3 Guillermina Lozano,2,3 and Mong-Hong Lee1,2,4*

Department of Molecular and Cellular Oncology,1 Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center,3 Programs in Cancer Biology,4 Genes & Development, University of Texas Graduate School of Biomedical Sciences, Houston, Texas2

Received 5 March 2003/ Returned for modification 21 April 2003/ Accepted 23 July 2003

The 14-3-3{sigma} (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3{sigma} is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3{sigma} was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3{sigma} in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3{sigma} has not yet been characterized. Here, we studied the link between 14-3-3{sigma} activities and p53 regulation. We found that 14-3-3{sigma} interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3{sigma} expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3{sigma} antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3{sigma} facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3{sigma} appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3{sigma} inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3{sigma} system. These results defined an important p53 regulatory loop and suggested that 14-3-3{sigma} expression can be considered for therapeutic intervention in cancers.

* Corresponding author. Mailing address: Box 79, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 794-1323. Fax: (713) 792-6059. E-mail: mhlee{at}notes.mdacc.tmc.edu.

Molecular and Cellular Biology, October 2003, p. 7096-7107, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7096-7107.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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