St. Jude Children's Research Hospital investigators have identified a novel structure in cells that serves as a control switch in the body's system for eliminating damaged cells and also offers new therapeutic potential.
The findings provide fresh insight into the machinery at work as cells ramp up production of p53 protein following DNA damage. The p53 protein plays a critical role in how cells respond to the stress that damages DNA. The gene that carries instructions for making p53 protein is the most commonly mutated gene in human cancers.
Investigators also identified molecules that disrupt the system and reduce p53 protein levels in cells damaged by irradiation or chemotherapy. These small molecules helped cells growing in the laboratory survive better after they were damaged. The findings appear in the September 13 online edition of the journal Genes & Development.
The work lays the foundation for a new approach to protecting healthy tissue using small molecules to reduce p53 protein levels in cells following damage caused by a wide range of factors, including the radiation and chemotherapy used to treat cancer or accidental exposure to dangerous chemicals or radiation, said Michael Kastan, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center and the paper's senior author. The same approach might also help ease the tissue damage that occurs as blood flow and oxygen are restored following a heart attack or stroke.
"We are excited about this because we now theoretically have a way of blunting p53 induction in settings where it is detrimental," he said.
The work builds on previous research from Kastan's laboratory into the mechanics of how p53 protein increases in response to cellular stress and DNA damage. Jing Chen, Ph.D., a postdoctoral fellow in Kastan's laboratory, is first author of the study.
The jump in p53 protein production was widely attributed to a decrease in the breakdo
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