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

m cells' proliferation and preventing them from replacing the blood cells lost to irradiation. "If the stem cells and their descendants are arrested for too long, they can't recover fast enough, and the mice eventually die of the effects of insufficient oxygenation of critical tissues," Wahl says.

The team then studied how p53 activation could cause these cells to arrest for too long. Using sophisticated new techniques, they found that p53 lacking its "dimmer switch" turned on too much of a gene called p21, which acts as a brake to halt cells from dividing. "To confirm the significance of that finding, we created mice that expressed the mutant p53, but had only one instead of the normal two copies of p21," Wahl says. "This reduced p21 levels after irradiation. Remarkably, this was enough to significantly reduce the mortality of the 'dimmerless' p53 mice. They were much less sensitive to radiation when they just had one less copy of p21."

The study underscores the importance of an evolutionarily conserved regulatory segment of p53 and the importance of p53 activity in the response to conditions that produce DNA damage. "Our study indicates that the amount of damaged DNA caused by radiation or toxins, isn't the sole determinant of life or death," says Wahl. "The extent to which p53 is also very important."

One implication of this research is that drugs to lower p53 levels, or to reduce its transcription of other growth-stopping genes such as p21, 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. "Our mouse model suggests that if you use a p53-activating agent, the last thing you should do is combine it with a general DNA-damaging chemotherapy or radiotherapy," Wahl says.


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Contact: Andy Hoang
ahoang@salk.edu
619-861-5811
Salk Institute
Source:Eurekalert

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