A protein known primarily for its role in fighting cancer also helps embryos implant in the womb, according to a study in mice. The find may explain why some women have difficulty becoming pregnant.
The p53 protein has been extensively studied for its involvement in several anticancer mechanisms, such as repairing DNA damage and initiating cell death to prevent the formation of tumors. (Mutations in the p53 gene can lead to cancer.) The p53 protein's function under normal conditions has remained a mystery, however. Last year, researchers led by reproductive endocrinologist Carolyn Coulam of the Rinehart Center for Reproductive Medicine in Evanston, Illinois, found an association between women carrying certain variations of p53 and problems conceiving, but the mechanism was unclear.
A team led by p53 co-discoverer and cancer biologist Arnold Levine of the Institute for Advanced Study in Princeton, New Jersey, subsequently noticed a link between p53 and fertility. The presence or absence of the gene seemed to have an effect on whether female mice could become pregnant. In the new study, the team dug deeper, comparing mice bred to lack p53 with normal mice. Whereas normal mice all became pregnant after breeding and had litters of five to six pups, just 63% of mice lacking p53 became pregnant and birthed litters of one or two pups. In another strain lacking p53, only 27% of the mice conceived and birthed pups.
Because the p53 protein fights cancer by regulating certain genes, the researchers thought that it likely had the same function in reproduction. A scan of possible target genes identified a suspect: the leukemia inhibitory factor (LIF) gene. LIF codes for a protein of the same name that helps embryos implant in the womb, as well as snuffing out certain leukemia cells.
Further experiments confirmed that p53 regulates LIF. Female mice lacking the p53 gene had lower levels of LIF in their uteri, corresponding to fewer embryo implantation sites. Administering LIF to these mice reversed their reproduction problems, improving their pregnancy rate to 100% and increasing their litter size, but had no effect on mice that carried the p53 gene, the researchers report in the 29 November issue of Nature.
Coulam says the newfound role of p53 may explain infertility cases that involve a failure of the embryo to implant. The findings also suggest a new role for cancer-treating drugs that target p53, adds developmental biologist Colin Stewart of the Institute of Medical Biology in Singapore. "Some of these drugs may turn out to be useful in helping women conceive by improving the function of p53 in the uterus. … Others may turn out to be possible contraceptives by blocking p53's function in the uterus."
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