No abstract

Activation of the p53 tumour suppressor is predicted to have therapeutically beneficial effects. Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway would open the way to long-term and possibly prophylactic treatments. We have established a simple protocol to screen small compound libraries for activators of p53-dependent transcription, and to select and characterise the most interesting hits, which include non-genotoxic activators. These compounds or their derivatives are of potential clinical interest. This approach may also lead to the identification of novel p53-activating compound families and possibly to the description of novel molecular pathways regulating p53 activity. ' 2005 Wiley-Liss, Inc.

The nuclear export inhibitor leptomycin B (LMB) prevents the export of proteins from the nucleus to the cytoplasm, protects p53 from Mdm2-mediated degradation and is a very potent inducer of the p53 transcriptional activity. Here we suggest that LMB can also interfere with the degradation of human Mdm2. In the presence of this drug, we observed two novel forms of this protein: a slow mobility form and an amino-terminal fragment with an apparent molecular mass of 32 kDa. The presence of this 32 kDa band is abolished with proteasome inhibitors, indicating that its appearance could be because of limited processing by the proteasome. These results may be useful in understanding the mechanism of degradation of Mdm2 by the proteasome.