Estrogen receptor protects p53 from deactivation by human double minute-2.
We and others have demonstrated that estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha is capable of binding hdm2 directly. The interaction of ERalpha and p53 does not interfere with the binding between p53 and hdm2; rather, these proteins form a ternary complex. The effect of ERalpha on the p53-hdm2 regulatory loop has been examined. Our results indicate that ERalpha protects p53 from being deactivated by hdm2. It is evident from these investigations that the ligand-independent protection of p53 by ERalpha 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.
Liu
G
G
Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Schwartz
J A
JA
Brooks
S C
SC
D001943:Breast Neoplasms; D047628:Estrogen Receptor alpha; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011960:Receptors, Estrogen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase