Details of a Death Warrant

When DNA is damaged beyond repair, cells commit suicide rather than run the risk of becoming cancerous. The p53 tumor-suppressor gene--so-called because it is lost or damaged in many cancers--issues the order to self-destruct. A report in today's issue of Nature describes how its order is carried out: The p53 protein turns on genes that unleash a highly toxic form of oxygen, destroying organelles and shredding cell membranes.

In order to determine how p53's sentence is executed, Kornella Polyak and colleagues at Johns Hopkins University condemned cells to death. They took cells from a colorectal cell line that lacks a working p53 gene, then infected them with either a p53-containing adenovirus or a control virus. The p53-infected cells went on to self-destruct, a process called apoptosis. But at least 8 hours before they self-destructed, the researchers looked at the messenger RNAs produced as genes were turned on in these cells. They then compared these mRNA levels with those in the control cells and found 14 genes that were expressed at levels 10-fold greater in the cells with p53 than in control cells.

Many of these genes, called PIGs for p53-induced genes, affect cellular levels of oxygen. For example, PIG1 belongs to a family of genes that can stimulate oxide production, and the closest relative of PIG3 in mammals is a potent generator of reactive oxygen species (ROS). When the researchers measured the concentration of ROS in the p53-expressing cell line, they found that it increased as apoptosis progressed, while the control cells showed no change. What's more, various inhibitors of ROS were shown to block apoptosis by 73% to 96%.

The finding is a "bold step" toward understanding how p53 leads to cell death, comments Andrew Wyllie of the University of Edinburgh in the United Kingdom. He would like to see the findings replicated in cells with their own intact p53 gene, but adds that drugs might one day be able to regulate p53 and prevent the cell death that occurs in heart attacks and strokes.

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