The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2.
Loss of function of the tumour suppressor gene p53 is a key event in most human cancers. Although usually occurring through mutation, in some tumour types this appears to be achieved via an indirect mechanism involving inappropriate expression of a functional inhibitor, mdm2, which binds to the transactivation domain of p53. This interaction offers an ideal potential target for novel cancer therapies. However, therapeutic specificity may depend on the extent to which this p53-inhibitory action of mdm2 is also required by normal cells. Transgenic data have already established that mdm2 is needed to prevent embryonic lethality, but the situation in adult cells is still unclear. Here we show that micro-injection of normal human fibroblasts with an antibody directed against the p53-binding domain of mdm2 induces expression of p53-responsive genes, and furthermore results in p53-dependent growth arrest. We conclude that normal cell proliferation can be dependent on negative regulation of p53 by mdm2, a finding which raises an important note of caution for mdm2-directed cancer therapies.
Department of Pathology, University of Wales College of Medicine, Cardiff, UK.
J P
JP
Blaydes
D
D
Wynford-Thomas
D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D000906:Antibodies; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2