Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 86
Effect of roscovitine on wt p53 protein in human MCF-7 breast cancer cells: uncoupling
of p53 nuclear accumulation and its activation by site-specific phosphorylation
Carmen Ranftler, Marieta Gueorguieva and Józefa W*sierska-G+dek
Cell Cycle Regulation Group, Division: Institute of Cancer Research, Department of
Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
We have recently observed activation of wt p53 protein in human MCF-7 breast cancer cells
upon treatment with roscovitine (ROSC), a potent cyclin-dependent inhibitor. ROSC is
known to inhibit the activating phosphorylation of the carboxy-terminal domain of RNA
polymerase II, thereby blocking the global transcription. It has been previously suggested that
ROSC-induced upregulation of p53 protein is attributable to the inhibition of transcription of
Mdm2, a negative p53 regulator. However, the analysis of the expression of p53-responsive
genes revealed that Mdm2 was upregulated in ROSC-treated MCF-7 cells. The kinetics of the
Mdm2 increase was slightly delayed as compared with that for p21waf1. Exposure of human
MCF-7 cells to different proteosome inhibitors resulted in the time-dependent increase of p53
levels. 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, proteosome inhibitors blocked cells in the S-phase, presumably due to the prevention of
cyclin degradation. Our results indicate that prevention of p53 degradation by proteasome
inhibitors does not mimic the action of ROSC.
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