p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding.
The tumour suppressor protein p53 is expressed at very low levels in normal cells but accumulates in response to DNA damaging agents such as u.v. irradiation. This increase is accompanied by transcriptional upregulation of the expression of a number of proteins including Mdm2 which can in turn inhibit p53 dependent transcriptional activation, creating a feedback loop resulting in down-regulation of p53 activity. Mutant p53 proteins are however frequently detected at constitutively high levels in many tumours and tumour cell lines, indeed this phenomenon has been used in several studies to diagnose p53 mutation in patient tumours. We show here that expression of mouse mutant p53 in tumour cell lines of this type results in high levels of both the endogenous p53 protein and the exogenously expressed mutant mouse protein, whereas the human tumour line MCF7 does not exhibit high levels of either endogenous human or exogenously expressed mouse mutant p53 unless stabilisation is induced by DNA damage. This suggests that the stability of mutant p53 is not intrinsic to mutant p53 protein structure but may vary in different cell backgrounds. We present evidence that p53 protein stability in tumour cell lines is determined by association with the Mdm2 tumour suppressor protein, and that p53 mutants which are unable to bind Mdm2 are stable in MCF7 cells. We propose that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals. MCF7 cells however express a transcriptionally active p53 and retain the feedback regulation of p53 protein levels by Mdm2.
Midgley
C A
CA
Department of Biochemistry, University of Dundee, UK.
Lane
D P
DP
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
D000952:Antigens, Polyomavirus Transforming; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2