p53: a new player in reproduction.

The roles of the p53 protein in tumor suppression have been firmly established. However, the functions of this protein under normal conditions or in the absence of stress, if any, have remained a mystery. In humans, some alleles containing a functional single nucleotide polymorphism in the p53 gene and its negative regulator, the Mdm2 gene, are under positive selection over evolutionary time frames, suggesting that the p53 pathway might have important functions that are optimized and selected for by evolutionary or reproductive pressures. Indeed, a recent study demonstrated a new function for the p53 protein in the regulation of maternal reproduction in mice, through transcriptional regulation of leukemia inhibitory factor (LIF), a novel p53 target gene. Sufficient uterine LIF levels are essential for the implantation of blastocysts or early embryos into the uterus. p53 deficient (p53(-/-)) female mice have a reduced pregnancy rate and litter size, due to impaired implantation resulting from decreased uterine LIF levels. Administration of LIF to pregnant p53(-/-) mice restored maternal reproduction by improving implantation. An association has been reported between women carrying the p53 codon 72 polymorphism (a proline to arginine change) with recurrent implantation failure, suggesting a similar function for p53 in humans. These findings of a new function for the p53 protein in reproduction may help to explain the observed evolutionary selection of some alleles of the p53 and Mdm2 genes. This may also be an excellent example of antagonistic pleiotrophy.