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Abstract
The 14-3-3σ (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 14-3-3σ is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3σ was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3σ in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3σ has not yet been characterized. Here, we studied the link between 14-3-3σ activities and p53 regulation. We found that 14-3-3σ interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3σ expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3σ antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3σ facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3σ appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3σ inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3σ system. These results defined an important p53 regulatory loop and suggested that 14-3-3σ expression can be considered for therapeutic intervention in cancers.
ACKNOWLEDGMENTS
We thank B. Vogelstein, M. Hung, and J. Wahl for valuable reagents.
This work was supported by the William McGowan Charitable foundation. H.-Y. Yang is a recipient of a postdoctoral fellowship from DOD Army Breast Cancer Research program (DAMD17-98-1-8243). M.-H. Lee is a recipient of a Flemin and Davenport research award and Susan G. Koman Breast Cancer Foundation research award.