ArticleOncogene2015
Mice engineered for an obligatory Mdm4 exon skipping express higher levels of the Mdm4-S isoform but exhibit increased p53 activity.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 35 citations in OpenAlex.
- Oncogenic and teratogenic effects ofeLife · 2025Article
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- A defective splicing machinery promotes senescence through MDM4 alternative splicing.Aging cell · 2024Article
- [Construction of an adenovirus vector expressing engineered splicing factor for regulating alternative splicing of YAP1 in neonatal rat cardiomyocytes].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2022Article
- Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death.Cell death and differentiation · 2022Article
- Alternative RNA splicing in tumour heterogeneity, plasticity and therapy.Disease models & mechanisms · 2022Review
- Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy.Neural regeneration research · 2021Review
- Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Zmat3 splices together p53-dependent tumor suppression.Molecular & cellular oncology · 2021Article
- Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program.Molecular cell · 2020Article
- PRMT1-p53 Pathway Controls Epicardial EMT and Invasion.Cell reports · 2020Article
- Germline mutation ofScience advances · 2020Article
- The long and the short of it: the MDM4 tail so far.Journal of molecular cell biology · 2019Review
- MiR-1205 functions as a tumor suppressor by disconnecting the synergy between KRAS and MDM4/E2F1 in non-small cell lung cancer.American journal of cancer research · 2019Article
- RNA Splicing and Disease: Animal Models to Therapies.Trends in genetics : TIG · 2019Review
- Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.Genes & development · 2018Article
- MDM4 contributes to the increased risk of glioma susceptibility in Han Chinese population.Scientific reports · 2018Article
- Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.Scientific reports · 2018Article
- A genome-wide siRNA screen for regulators of tumor suppressor p53 activity in human non-small cell lung cancer cells identifies components of the RNA splicing machinery as targets for anticancer treatment.Molecular oncology · 2017Article
- Tumorigenesis promotes Mdm4-S overexpression.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mdm4, a protein related to the ubiquitin-ligase Mdm2, is an essential inhibitor of tumor suppressor protein p53. In both human and mouse cells, the Mdm4 gene encodes two major transcripts: one encodes the full-length oncoprotein (designated below as Mdm4-FL), whereas the other, resulting from a variant splicing that skips exon 6, encodes the shorter isoform Mdm4-S. Importantly, increased Mdm4-S mRNA levels were observed in several human cancers, and correlated with poor survival. However, the role of Mdm4-S in cancer progression remains controversial, because the Mdm4-S protein appeared to be a potent p53 inhibitor when overexpressed, but the splice variant also leads to a decrease in Mdm4-FL expression. To unambiguously determine the physiological impact of the Mdm4-S splice variant, we generated a mouse model with a targeted deletion of the Mdm4 exon 6, thereby creating an obligatory exon skipping. The mutant allele (Mdm4(ΔE6)) prevented the expression of Mdm4-FL, but also led to increased Mdm4-S mRNA levels. Mice homozygous for this allele died during embryonic development, but were rescued by a concomitant p53 deficiency. Furthermore in a hypomorphic p53(ΔP/ΔP) context, the Mdm4(ΔE6) allele led to p53 activation and delayed the growth of oncogene-induced tumors. We next determined the effect of Mdm4(+/ΔE6) heterozygosity in a hypermorphic p53(+/Δ31) genetic background, recently shown to be extremely sensitive to Mdm4 activity. Mdm4(+/ΔE6) p53(+/Δ31) pups were born, but suffered from aplastic anemia and died before weaning, again indicating an increased p53 activity. Our results demonstrate that the main effect of a skipping of Mdm4 exon 6 is not the synthesis of the Mdm4-S protein, but rather a decrease in Mdm4-FL expression. These and other data suggest that increased Mdm4-S mRNA levels might correlate with more aggressive cancers without encoding significant amounts of a potential oncoprotein. Hypotheses that may account for this apparent paradox are discussed.
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