Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms

The growth, division and eventual death of the cells in the body are processes that are tightly controlled by hundreds of genes working together. If any of these genes are switched on (or off) in the wrong cell or at the wrong time, it can lead to cancer. It has been known for many years that the protein encoded by one gene in particular—called p53—is nearly always switched off in cancer cells. The p53 protein normally acts like a ‘brake’ to slow the uncontrolled division of cells, and some researchers are working to find ways to switch on this protein in cancer cells. However, this approach appears to only work in specific cases of this disease. For better results, we need to understand how p53 is normally switched on, and what other genes this protein controls once it is activated. Allen et al. have now identified the genes that are directly switched on when cancer cells are treated with a drug that artificially activates the p53 protein. Nearly 200 genes were switched on, and almost three quarters of these genes had not previously been identified as direct targets of p53. Although p53 tends to act as a brake to slow cell division, it is not clear how it distinguishes between its target genes—some of which promote cell survival, while others promote cell death. Allen et al. found that survival genes are switched on more strongly than cell death genes via a range of different mechanisms; this may explain why most cancers can survive drug treatments that reactivate p53. Also, Allen et al. revealed that some p53 target genes are primed to be switched on, even before the p53 protein is activated, by proteins (and other molecules) acting in regions of the DNA outside of the genes. By uncovering many new gene targets for the p53 protein, the findings of Allen et al. could help researchers developing new drugs or treatments for cancer.