The p53-MDM2 interaction in a cancer-prone family, and the identification of a novel therapeutic target.
One approach to developing novel anti-cancer agents is to identify and characterise targets that directly regulate cell growth and are dysfunctional in the disease state. One such target is the interaction between the p53 tumour suppressor and the oncogene product of the murine double minute gene, MDM2. MDM2 is known to bind wild-type p53 and block the transcriptional activation of p53-dependent genes. We have previously described a cancer-prone family with elevated levels of wild-type p53, and now show that MDM2 is also over-expressed in the proband from this family. Interestingly, the overexpression of MDM2 is independent of other p53-regulated genes such as p21WAF1. The present work and a review of recent insights into the p53-MDM2 interaction, and p53 transcriptional activity, identify a new target site for the rational development of novel anti-cancer agents.
Picksley
S M
SM
Department of Biochemistry, University of Dundee, UK.
Spicer
J F
JF
Barnes
D M
DM
Lane
D P
DP
D000970:Antineoplastic Agents / Q000138:chemical synthesis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007890:Leiomyosarcoma / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011519:Proto-Oncogenes / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2