Prevention of p53 degradation in human MCF-7 cells by proteasome inhibitors does not mimic the action of roscovitine.

We have recently observed activation of wild-type (wt) p53 protein in human MCF-7 breast cancer cells upon treatment with roscovitine (ROSC), a potent cyclin-dependent kinase inhibitor. It has been previously suggested that ROSC repressed transcription of Mdm-2, a negative p53 regulator, and that the lack of Mdm-2 contributes to the ROSC-induced upregulation of p53 protein. Therefore, we decided to see whether the prevention of p53 degradation by proteasome inhibitors will mimic the effects generated by ROSC. Exposure of human MCF-7 cells to different proteasome inhibitors resulted in a time-dependent increase of p53. However, unlike ROSC, they failed to modify p53 protein at Ser46 and to induce p53AIP1 protein. Moreover, whereas ROSC arrested MCF-7 cells in the G2-phase of the cell cycle, proteasome inhibitors blocked cells primarily in the S-phase, presumably because of the prevention of cyclin degradation. Our results indicate that prevention of p53 degradation by proteasome inhibitors does not mimic the action of ROSC.