A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection
Open accessAbstract
The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.
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p53 activates PGF, TGFA and KITLG that encode growth factors that can stimulate cell proliferation.
“Notably, p53 also activates PGF,160 TGFA161 and KITLG50 that encode for growth factors that can stimulate cell proliferation.”
From Census and evaluation of p53 target genes (2017) · cites this paper as [50]
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References 79 · Cited by 118
- Authors
- Zeron-Medina, J., Wang, X., Repapi, E., Campbell, M. R., Su, D., Castro-Giner, F., Davies, B., Peterse, E. F. P., Sacilotto, N., Walker, G. J., Terzian, T., Tomlinson, I. P., Box, N. F., Meinshausen, N., De Val, S., Bell, D. A., & Bond, G. L.
- Affiliations
- National Institutes of Health (US)
- University of Oxford (GB)
- Centre for Human Genetics (GB)
- QIMR Berghofer Medical Research Institute (AU)
- University of Colorado Denver (US)
- Corresponding author
- Bell, Douglas A.
- Bond, Gareth L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 155
- Issue
- 2
- Pages
- 410-422
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4171736
- OpenAlex
- W2063475603
- Cited by
- 118
- References
- 79
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 14 · 2016: 16 · 2015: 18 · 2014: 23 · 2013: 1
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust (090532, 090532/Z/09/Z)
- British Heart Foundation (PG/10/83/28610)
- National Institutes of Health (Z01-ES100475)
- Medical Research Council (MR/J007765/1)
- National Institute of Environmental Health Sciences (Z01ES046008, ZIAES046008, Z01ES100475, ZIAES100475)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR057212, K01AR063203)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- p53, stem cell factor, single nucleotide polymorphisms, cancer susceptibility, natural selection, positive selection, negative selection, transcriptional regulation, tumor suppression
- MeSH terms
- Animals, Humans, Male, Selection, Genetic, Testicular Neoplasms, Transcription, Genetic, Tumor Suppressor Protein p53, Stem Cell Factor, Genetic Predisposition to Disease, Response Elements, Polymorphism, Single Nucleotide, Cell Proliferation, Mice, Genome-Wide Association Study
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