Alternative fuel--another role for p53 in the regulation of metabolism

The role of the p53 protein in preventing tumor progression has been largely attributed to its ability to induce apoptosis or senescence in cells undergoing malignant progression (1). The transformation of cells from normal to cancerous is accompanied by increases in numerous types of stress that signal to the activation of p53, which can then provoke the elimination of the rogue cell. This executioner role for p53 neatly accommodates its role as a tumor suppressor—and it is certainly the response to p53 that we would like to reactivate for the treatment of cancer. However, there is now growing evidence that under certain circumstances, p53 can also come to the aid of a stressed cell, functioning to protect the cell from damage and contributing to a survival response (2). Several of the more recently described roles of p53 in regulating metabolism seem to fall into this latter category, suggesting that p53 helps to maintain normal metabolism and plays a key role in allowing cells to adapt to various types of metabolic stress. Two interesting new studies published in this issue of PNAS take this area of p53 activity even further, describing a role for p53 in the metabolism of glutamine through the activation of expression of glutaminase 2 (GLS2) (3, 4). These observations immediately suggest a plethora of intriguing possibilities and further questions. p53 is a key player in the response to a multitude of different types of stress. First shown to be activated by DNA damage, we now know that p53 can be induced by a broad gamut of signals, including telomere shortening, hypoxia, loss of cell contact, oncogene activation, and starvation. It seems that whenever the cell gets into trouble, p53 is called upon to help deal with the problem. Interestingly, the range of possible outcomes upon p53