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The genome guardian's dimmer switch: regulating p53 is a matter of life or death

Cell

Geoffrey M. Wahl

A team of scientists led by Geoffrey M. Wahl has found clues to the functioning of an important damage response protein in cells. Although the protein, p53, is known as an important tumor suppressor, it is also critical for determining whether a cell survives stress and continues to function in a variety of situations. Wahl's study, which appeared in the journal Genes & Development, shows that a short segment on p53 acts as a dimmer switch that helps control the level of p53 activity in a critical stem cell population and the offspring they generate.

One vexing problem with p53 is that it apparently evolved to protect the integrity of the genome for future generations rather than to prolong the lives of individual cells or animals, so from the point of view of an animal, p53 sometimes goes too far in killing cells or suppressing growth. Experiments in mice have suggested that even modest reductions in p53's activity greatly increases survival after exposure to radiation without raising the long-term cancer risk to unacceptable levels.

Scientists therefore are eager to find out how cells regulate p53, so they can target these mechanisms with drugs. Wahl and colleagues, including postdoc Vivian Wang and Kenneth Kaushansky, M.D., a past president of the American Society for Hematology and former faculty member at UC San Diego, set out to illuminate the function of a stretch of regulatory amino acids at one end of the protein by creating "designer" mice with other amino acids in this region, thereby rendering it inoperative. What they found was that irradiation and the ensuing p53 response significantly damaged the blood-forming cells of the mice's bone marrow, but other parts of their bodies seemed normal. The results led the team to conclude that the loss of function of p53's normal "dimmer-switch" segment had allowed the protein to become too active, arresting the hematopoietic stem cells' proliferation and preventing them from replacing blood cells lost to irradiation.

One implication of the research is that drugs to lower p53 levels, or to reduce its transcription of other growth-stopping genes, might be used temporarily to reduce unwanted tissue damage from DNA-altering drugs or radiation. Another implication is that p53-boosting drugs, which are currently being tested in cancer patients, could have dangerous side effects if used in combination with other drugs that cause DNA damage.