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Estrogen Receptor Protects p53 from Deactivation by Human Double Minute-2¹

Graduate Program in Cancer Biology [G. L.], Department of Physiology [J. A. S.], Department of Biochemistry and Molecular Biology [S. C. B.], and the Barbara Ann Karmanos Cancer Institute [J. A. S., S. C. B.], Wayne State University School of Medicine, Detroit, Michigan 48201

We and others have demonstrated that estrogen receptor (ER) and p53, two important regulatory proteins in breast cancer, bind to each other. In this report, using the glutathione S-transferase pull-down methodology, we show the ligand-independent interaction of ER with the NH₂-terminal region of p53, a region known to bind the p300 and human double minute-2 (hdm2) regulatory factors. Furthermore, we have demonstrated that ER is capable of binding hdm2 directly. The interaction of ER and p53 does not interfere with the binding between p53 and hdm2; rather, these proteins form a ternary complex. The effect of ER on the p53-hdm2 regulatory loop has been examined. Our results indicate that ER protects p53 from being deactivated by hdm2. It is evident from these investigations that the ligand-independent protection of p53 by ER is a novel role for this protein in addition to its classic regulatory function as a ligand-inducible transcription factor. This study also describes a new mechanism of cellular regulation of p53 activity.

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