The Role of p53 Gene Family in Reproduction

Abstract

The p53 family of genes ( p53, p63, and p73) is conserved over evolutionary time scales. Although the functions of p53 gene and its protein as a tumor suppressor have been firmly established, the earliest functions for the p53 ancestral genes in worms and flies are to ensure germ-line genomic integrity and the fidelity of the developmental process. In vertebrates, the p53 family of genes retains those functions in germ-line genomic integrity but have added important functions in regulation of reproduction. Loss of the p53, p63, or p73 genes in female mice leads to a significant decrease of fertility. The p53 gene product regulates maternal reproduction at the implantation stage of the embryo. p63 and p73 play important roles in monitoring the genomic quality of oocytes. The p53 pathway appears to play a similar role in human fertility. In humans, certain alleles containing a functional single-nucleotide polymorphism (SNP) in the p53 pathway are under positive evolutionary selection. Selected alleles of these SNPs in the p53 pathway are associated with decreased fertility. This important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway. These observations provide a good possible example of antagonistic pleiotrophy for fertility, tumor suppression, and longevity.

Increased apoptosis in bovine blastocysts exposed to high levels of IGF1 is not associated with downregulation of the IGF1 receptor

“…However, recent data suggest that TP53 does not act merely as a death signal, but rather as a modulator of damage responses to ensure successful development (Toyoshima 2009). It has been suggested that the primordial function of the TP53 ancestor gene was to ensure fecundity and production of normal offspring and that its function as a tumour suppressor came later in evolution (Hu 2009). Accordingly, there is evidence indicating that expression of TP53 is essential for female fertility (Hu et al 2007) and that active TP53-dependent cell death signalling is required to suppress erroneous replication of damaged DNA during the preimplantation period (Toyoshima 2009) and to avoid abnormalities during foetal development (Torchinsky & Toder 2010).…”

Maternal SNPs in the p53 Pathway: Risk Factors for Trisomy 21?

“…Even if the inactivation of p53 is not the primary cause of aneuploidy, its dysfunction strongly facilitates a tolerance to this chromosomal instability [5] and, 2) Loss of p73 function due to polymorphisms in its encoding gene may interfere in the control of the meiotic spindle during oogenesis, increasing the risk of aneuploidy in the offspring [56,57]. The expression of TP73 naturally decreases with age, therefore the loss of TP73 function may contribute to the increase of aneuploidy produced by old oocytes [26,56,57]. In our sample about 43% of women were younger than 35 years at the time of the trisomic fetus conception.…”

“…Recent evidence has shown the important role played by p53 family as regulators of crucial processes related to human reproduction [14,26]. Our working hypothesis was based on two main pieces of evidence: 1) The loss of p53 function or genes that regulate this metabolic pathway may be related to the accumulation of aneuploid cells, increasing the risk of DS birth in women with these polymorphisms [55].…”

“…Genomic instability, aneuploidy and copy number polymorphisms that originate in the female germline and contribute to a number of developmental defects can be explored through investigations of the TP53 gene family [26]. Encoded by TP53 gene, the p53 protein has known importance in the prevention of tumors and genomic stability in somatic cells, acting as a transcription factor that regulates a large number of genes in response to cell damage, including activation of oncogenes and DNA damage [12,35,45].…”

The Regulation of Aging and Longevity: A New and Complex Role of p53

“…Indeed, recent studies have shown that p53 and its family members, including p63 and p73, all play important roles in reproduction. [10][11][12][13] Recent studies have also suggested that p53 plays a role as a longevity regulator. It has been well established that p53 has a profound impact on longevity in different organisms through its tumor-suppressive function.…”