Regulation of Fertility by the p53 Family Members

Abstract

The p53 family members, which consist of 3 transcription factors-p53, p63, and p73-are conserved during evolution. The p53 family proteins are involved in many important cellular functions, including tumor suppression (p53 and p73), the development of epithelial cell layers (p63), and the development of central nervous system and immune system (p73). Studies on p53-like proteins in low organisms have demonstrated that their primordial functions are to maintain the genomic integrity of germ cells and ensure faithful development and reproduction. In vertebrates, the p53 family proteins retain these functions in reproduction and at the same time have developed additional important functions in reproduction, such as the regulation of embryonic implantation (p53). p53 regulates embryonic implantation through transcriptional regulation of leukemia inhibitory factor (LIF). p63, in particular TAp63, is a main regulator to protect the fidelity of female germ cells during meiotic arrest. p73, in particular TAp73, regulates the ovary function and the quality of oocytes. Loss of p53, p63, or p73 genes in female mice leads to a significant decrease in fertility. These functions of the p53 family proteins in reproduction provide a plausible explanation for positive evolutionary selection observed in a group of single nucleotide polymorphisms and haplotypes in the p53 family genes. A better understanding of the functions of the p53 family proteins in reproduction may lead to new strategies for fertility treatment.

p53 genes function to restrain mobile elements

“…Consistent with previous reports (Hu et al 2011), we observed partial infertility phenotypes in p53 − female flies that were rescued in p53Rescue strains (see the Materials and Methods; Supplemental Table 2). Thus, in Drosophila, p53 loss permits widespread dysregulation of retroelements and associated phenotypes.…”

“…Viewed from this perspective, transposon eruptions in the germline are consistent with infertility phenotypes seen in p53 − flies, zebrafish, and mice (see the Materials and Methods; Supplemental Tables 2,4) (Hu et al 2011). Combined, these observations suggest that p53-mediated tumor suppression was evolutionarily co-opted from ancestral meiotic functions that restricted mobile elements to insure germline integrity.…”

The Regulation of Multiple p53 Stress Responses is Mediated through MDM2

“…In humans and mice, all 3 of the p53/p63 and p73 gene products continue to play a role in the functions of the female germline and implantation of fertilized eggs. 106 In humans, what are the functions of the p53 protein? Is it more than protecting us from cancers?…”

TP53 Gene Polymorphisms in Cancer Risk: The Modulating Effect of Ageing, Ethnicity and TP53 Somatic Abnormalities

“…Interestingly, the frequency of the G allele has been positively correlated with low winter temperatures (Shi et al, 2009). In this respect, northern populations living in cold climates and having a high percentage of G alleles could be at an advantage due to a reduced risk of implantation failure Hu et al, 2011). Additionally, it is critical to note that the geographic distribution of rs1042522 alleles is also linked with the capacity of p53 to regulate pigmentation and sunburn resistance through the activation of tyrosinase, the ratelimiting enzyme for melanin synthesis, and by induction of transcription of the melanogenic cytokine pro-opiomelanocortin (Hirshfield et al, 2010;Khlgatian et al, 2002;Murase et al, 2009).…”

“…As noted in previous sections of this review, the functionally different p53 polymorphic proteins have the advantage of depending on specific environmental conditions (Hirshfield et al, 2010;Hu et al, 2011;Jeong et al, 2010). In addition, www.intechopen.com manifestation of the cancer predisposing effects of TP53 polymorphisms may also be altered between the different ethnic groups (Weston et al, 1997).…”