Fluorescence polarization assay and inhibitor design for MDM2/p53 interaction

MDM2 is an important negative regulator of the tumor suppressor protein p53 which regulates the expression of many genes including MDM2. The delicate balance of this autoregulatory loop is crucial for the maintenance of the genome and control of the cell cycle and apoptosis. MDM2 hyperactivity, due...

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Bibliographic Details
Published in:Analytical biochemistry 2004-08, Vol.331 (1), p.138-146
Main Authors: Zhang, Rumin, Mayhood, Todd, Lipari, Philip, Wang, Yaolin, Durkin, James, Syto, Rosalinda, Gesell, Jennifer, McNemar, Charles, Windsor, William
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Cell Cycle - physiology
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Fluorescence Polarization
Humans
Neoplasms - drug therapy
Neoplasms - metabolism
Nuclear Proteins - antagonists & inhibitors
Nuclear Proteins - chemistry
Nuclear Proteins - metabolism
Peptides - chemistry
Protein Binding
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2
Tumor Suppressor Protein p53 - chemistry
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Summary:MDM2 is an important negative regulator of the tumor suppressor protein p53 which regulates the expression of many genes including MDM2. The delicate balance of this autoregulatory loop is crucial for the maintenance of the genome and control of the cell cycle and apoptosis. MDM2 hyperactivity, due to amplification/overexpression or mutational inactivation of the ARF locus, inhibits the function of wild-type p53 and can lead to the development of a wide variety of cancers. Thus, the development of anti-MDM2 therapies may restore normal p53 function in tumor cells and induce growth suppression and apoptosis. We report here a novel high-throughput fluorescence polarization binding assay and its application in rank ordering small-molecule inhibitors that block the binding of MDM2 to a p53-derived fluorescent peptide.
ISSN:0003-2697
1096-0309
DOI:10.1016/S0003-2697(04)00223-4