The p53-Mdm2 pathway: targets for the development of new anticancer therapeutics.
The tumour suppressor p53 is at the centre of a network of regulatory pathways that guard over the continued integrity of the living cell and its progeny after exposure to different forms of stress, particularly those capable of inducing DNA damage. Tumour cells very frequently circumvent this control by disabling the function of p53, or other proteins in the p53 network, through mutation. Here we review the different therapeutic strategies that have been adopted to exploit common neoplastic aberrations in the p53 pathways. We emphasise in particular those approaches where modulation with pharmaceutical agents has already shown some promise, including pharmacological rescue of mutant p53, modulation of the protein-protein interaction between p53 and one of its negative regulators, Mdm2, as well as interference with downstream targets.
Zheleva
Daniella I
DI
Cyclacel Limited, James Lindsay Place, Dundee, Scotland, UK.
Lane
David P
DP
Fischer
Peter M
PM
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2