Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans
Open accessAbstract
The tumor suppressor protein p53 plays an important role in maternal reproduction in mice through transcriptional regulation of leukemia inhibitory factor (LIF), a cytokine crucial for blastocyst implantation. To determine whether these observations could be extended to humans, a list of single-nucleotide polymorphisms (SNPs) in the p53 pathway that can modify the function of p53 was assembled and used to study their impact on human fertility. The p53 allele encoding proline at codon 72 (P72) was found to be significantly enriched over the allele encoding arginine (R72) among in vitro fertilization (IVF) patients. The P72 allele serves as a risk factor for implantation failure. LIF levels are significantly lower in cells with the P72 allele than in cells with the R72 allele, which may contribute to the decreased implantation and fertility associated with the P72 allele. Selected alleles in SNPs in LIF, Mdm2, Mdm4, and Hausp genes, each of which regulates p53 levels in cells, are also enriched in IVF patients. Interestingly, the role of these SNPs on fertility was much reduced or absent in patients older than 35 years of age, indicating that other functions may play a more important role in infertility in older women. The association of SNPs in the p53 pathway with human fertility suggests that p53 regulates the efficiency of human reproduction. These results also provide a plausible explanation for the evolutionary positive selection of some alleles in the p53 pathway and demonstrate the alleles in the p53 pathway as a good example of antagonistic pleiotropy.
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p53 may take part in other essential physiological processes, such as stem cell homeostasis and fertility.
“There is increasing evidence that in addition to the ‘classical’ function of p53 in the DNA damage response, this versatile protein might be involved in other essential physiological processes, including stem cell homeostasis and fertility [106–108].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [106]
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- Authors
- Kang, H.-J., Feng, Z., Sun, Y., Atwal, G., Murphy, M. E., Rebbeck, T. R., Rosenwaks, Z., Levine, A. J., & Hu, W.
- Affiliations
- Weill Cornell Medicine (US)
- Rutgers Cancer Institute (US)
- Institute for Advanced Study (US)
- Fox Chase Cancer Center (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-06-16
- Volume
- 106
- Issue
- 24
- Pages
- 9761-9766
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2700980
- OpenAlex
- W1972013614
- Cited by
- 193
- References
- 22
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 13 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 9 · 2018: 14 · 2017: 7 · 2016: 11 · 2015: 12 · 2014: 15 · 2013: 12 · 2012: 24
- FWCI
- 22.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (R01CA102184)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p53, single nucleotide polymorphisms, human fertility, leukemia inhibitory factor, embryo implantation, implantation failure, in vitro fertilization, p53 codon 72, MDM2, MDM4, USP7, maternal reproduction, maternal age, positive selection, antagonistic pleiotropy, genetic association
- MeSH terms
- Alleles, Codon, Fertility, Fertilization in Vitro, Humans, Embryo Implantation, Tumor Suppressor Protein p53, Polymorphism, Single Nucleotide, Leukemia Inhibitory Factor
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