Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3

John T. Patton, Lindsey D. Mayo, Aatur D. Singhi, Andrei V. Gudkov, George R. Stark, Mark W. Jackson

Research output: Contribution to journalArticle

160 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3169-3176
Number of pages8
JournalCancer Research
Volume66
Issue number6
DOIs
StatePublished - Mar 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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