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The genome guardian's dimmer switch: Regulating p53 is a matter of life or death
Date:6/30/2011

iation, without raising the long-term cancer risk to unacceptable levels.

Scientists therefore are eager to find out how cells naturally regulate p53, so that they can target these mechanisms with drugs. One clue uncovered by recent studies is that regulatory molecules can alter p53 activity by chemically modifying some key amino acids. In the current study, Wahl and colleagues 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.

The mutant mice had somewhat higher p53 activity than normal mice, at least in some tissues. Based on other studies, Wahl's team expected the mutants to age faster. To their surprise, however, the mutant mice lived about as long as ordinary, "wild type" mice. A second surprise came when Wahl's team exposed the mice to ionizing radiation, of the sort that nuclear power plants may emit. While all the normal mice survived, half the mutant mice died within four weeks.

To understand why the mutant mice died so readily, Vivian Wang, a postdoc in Wahl's lab, collaborated with the Salk veterinarian, Mat Leblanc, and hematologists at UCSD and noted that the irradiated mutant mouse hearts became enlarged and pale, as if they had been starved of oxygen. "Eventually, we found the reason for this," Wahl explains. "We found that irradiation and the ensuing p53 response significantly damaged the blood-forming cells of their bone marrow, but other parts of their bodies seemed quite normal. We followed up these studies with stem cell transplantation experiments to show the mutant p53 really affected the stem cells and their descendents that make the blood."

These 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 in the hematopoietic stem cells of the mutant mice, arresting the ste
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Contact: Andy Hoang
ahoang@salk.edu
619-861-5811
Salk Institute
Source:Eurekalert

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