The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation

Area of Science:

• Molecular Biology
• Oncology
• Cellular Biology

Background:

• The p53 protein is a critical tumor suppressor.
• The murine double minute 2 (mdm-2) gene encodes a protein that can enhance tumorigenic potential when overexpressed.
• mdm-2 is a putative transcription factor.

Purpose of the Study:

• To characterize and identify a cellular phosphoprotein that complexes with p53.
• To investigate whether mdm-2 can modulate p53 transactivation.
• To determine the functional consequence of the mdm-2/p53 interaction.

Main Methods:

• Purification and characterization of a 90-kd phosphoprotein (p90) that complexes with p53.
• Identification of p90 as a product of the mdm-2 gene.
• Co-transfection assays using a p53-responsive element from the muscle creatine kinase gene and plasmids expressing wild-type p53 and mdm-2.

Main Results:

• A 90-kd phosphoprotein was purified and identified as a product of the mdm-2 gene.
• mdm-2 product forms a tight complex with both mutant and wild-type p53.
• Overexpression of mdm-2 inhibited p53-mediated transactivation of a p53-responsive element.

Conclusions:

• The mdm-2 oncogene product directly interacts with the p53 protein.
• mdm-2 inhibits the transcriptional activity of p53.
• This interaction suggests a mechanism by which mdm-2 contributes to tumorigenesis by inactivating p53.