Analysis of MDM2 and MDM4 Single Nucleotide Polymorphisms, mRNA Splicing and Protein Expression in Retinoblastoma
Open accessAbstract
Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. Biallelic RB1 gene inactivation is the initiating genetic lesion in retinoblastoma. The p53 gene is intact in human retinoblastoma but the pathway is believed to be suppressed by increased expression of MDM4 (MDMX) and MDM2. Here we quantify the expression of MDM4 and MDM2 mRNA and protein in human fetal retinae, primary retinoblastomas, retinoblastoma cell lines and several independent orthotopic retinoblastoma xenografts. We found that MDM4 is the major p53 antagonist expressed in retinoblastoma and in the developing human retina. We also discovered that MDM4 protein steady state levels are much higher in retinoblastoma than in human fetal retinae. This increase would not have been predicted based on the mRNA levels. We explored several possible post-transcriptional mechanisms that may contribute to the elevated levels of MDM4 protein. A proportion of MDM4 transcripts are alternatively spliced to produce protein products that are reported to be more stable and oncogenic. We also discovered that a microRNA predicted to target MDM4 (miR191) was downregulated in retinoblastoma relative to human fetal retinae and a subset of samples had somatic mutations that eliminated the miR-191 binding site in the MDM4 mRNA. Taken together, these data suggest that post-transcriptional mechanisms may contribute to stabilization of the MDM4 protein in retinoblastoma.
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Many tumours exhibit high MDM2 and MDMX protein levels without increased copy number, including melanoma, Ewing's sarcoma, colon carcinoma and retinoblastoma.
“However, many tumours exhibit high MDM2 and MDMX protein levels without increased copy number. These include melanoma10, Ewing's sarcoma22, colon carcinoma9 and retinoblastoma12,23.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [23]
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References 26 · Cited by 80
Research works printed but not linked: 1
- [27]Rallapalli R, Strachan G, Cho B, Mercer WE, Hall DJ (1999) A novel MDMX transcript expressed in a variety of transformed cell lines encodes a truncated protein with potent p53 repressive activity. The Journal of biological chemistry 274: 8299– 8308. 10075736
- Authors
- McEvoy, J., Ulyanov, A., Brennan, R., Wu, G., Pounds, S., Zhang, J., & Dyer, M. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Dyer, Michael A.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-08-20
- Volume
- 7
- Issue
- 8
- Pages
- e42739
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3423419
- OpenAlex
- W2022929716
- Cited by
- 80
- References
- 26
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 10 · 2013: 8
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- Research to Prevent Blindness (CA21765)
- American Lebanese Syrian Associated Charities (CA 21765)
- National Institutes of Health (CA21765))
- National Eye Institute (EY014867, R01EY014867, R01EY018599, EY018599)
- National Cancer Institute (CA21765, P30CA021765)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- retinoblastoma, MDM2, MDM4, single nucleotide polymorphisms, mRNA splicing, alternative splicing, protein stability, post-transcriptional regulation, miR-191, somatic mutations, fetal retina, RB1 inactivation
- MeSH terms
- Binding Sites, Genotype, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Retinoblastoma, RNA Splicing, RNA, Messenger, DNA Primers, Cell Cycle Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-mdm2, Real-Time Polymerase Chain Reaction
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