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Cell, Tumor, and Stem Cell Biology |
1 Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation and Departments of 2 Genetics and 3 Radiation Oncology and Pharmacology, Case Western Reserve University, Case Comprehensive Cancer Center, Cleveland, Ohio
Requests for reprints: Mark W. Jackson, Department of Molecular Genetics, Lerner Research Institute/NC20, Cleveland Clinic Foundation, 9500, Euclid Avenue, Cleveland, OH 44195. Phone: 216-368-5674; Fax: 216-368-8919; E-mail: mwj7{at}cwru.edu.
Hdm2 and HdmX coordinately regulate the stability and function of p53. Each is overexpressed in subsets of many different types of malignancy, and most of these subsets maintain wild-type p53. Nutlins, newly discovered small-molecule inhibitors of the Hdm2-p53 interaction, offer a novel strategy for therapy of tumors with wild-type p53. We now show that Nutlin-3 efficiently induces apoptosis and diminishes long-term survival of human fibroblasts transformed in vitro by Hdm2 but not HdmX. The resistance of cells overexpressing HdmX to Nutlin-3 is due to its inability to disrupt the p53-HdmX interaction, resulting in continued suppression of p53 activity. Although HdmX overexpression yielded cells resistant to Nutlin-3, ablation of HdmX expression by short hairpin RNA sensitized tumor cells to Nutlin-3–mediated cell death or arrest. Furthermore, deletion of the COOH-terminal RING finger domain of HdmX completely reversed the resistance to Nutlin-3, probably reflecting the requirement of the RING finger for interaction with Hdm2. Thus, the relative abundance of Hdm2 and HdmX and the specificity of Nutlin-3 for Hdm2 influence the sensitivity of cells to p53-dependent apoptosis or arrest in response to Nutlin-3. Our findings establish Hdm2 and HdmX as independent therapeutic targets with respect to reactivating wild-type p53 as a means for cancer therapy. (Cancer Res 2006; 66(6): 3169-76)
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