The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 
repressor MDM2, varies widely among human cancer-derived cell types. Whereas 
HCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 
leukemia cells undergo rapid apoptosis and other cell lines show an intermediate 
response. We found that the expression of the p53 target genes p21, 14-3-3sigma 
and the microRNA miR-34a correlates tightly with the cell fate choice adopted. 
All three genes were strongly induced in arresting cells, but silenced in cells 
undergoing Nutlin-3-induced apoptosis. In contrast, key apoptotic p53 target 
genes were equally expressed in arresting and apoptotic cells. Interestingly, we 
establish that miR-34a cooperates with p21 and 14-3-3sigma to override the 
apoptotic signals generated by p53 activation. Strikingly, p53 binding to 
chromatin and p53-mediated recruitment of certain coactivators to all three 
target loci does not vary among cell types. Instead, the cell type-specific 
silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma 
promoter DNA methylation and reduced processing of the miR-34a primary 
transcript. Thus, p53-independent events regulating expression of protein-coding 
genes and microRNAs within the network can define the cellular outcome of p53 
activation.