Drug discovery and mutant p53.
Missense mutations in the p53 gene are commonly selected for in developing human cancer cells. These diverse mutations in p53 can inactivate its normal sequence-specific DNA-binding and transactivation function, but these mutations can also stabilize a mutant form of p53 with pro-oncogenic potential. Recent multi-disciplinary advances have demonstrated exciting and unexpected potential in therapeutically targeting the mutant p53 pathway, including: the development of biophysical models to explain how mutations inactivate p53 and strategies for refolding and reactivation of mutant p53, the ability of mutant p53 protein to escape MDM2-mediated degradation in human cancers, and the growing 'interactome' of mutant p53 that begins to explain how the mutant p53 protein can contribute to diverse oncogenic and pro-metastatic signaling. Our rapidly accumulating knowledge on mutant p53-signaling pathways will facilitate drug discovery programmes in the challenging area of protein-protein interactions and mutant protein conformational control.
Maslon
Magda M
MM
University of Edinburgh, Institute of Genetics and Molecular Medicine, Cell Signalling Unit, Cancer Research UK p53 Signal Transduction Group, Edinburgh EH4 2XR, UK.
Hupp
Ted R
TR
D055808:Drug Discovery; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2