TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions
- Cold Spring Harbor Laboratory, United States
- Memorial Sloan Kettering Cancer Center, United States
- University of Ljubljana, Slovenia
Abstract
TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.
Data availability
-
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid LeukemiaPublicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive Molecular Portraits of Invasive Lobular Breast CancerPublicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive molecular characterization of human colon and rectal cancer.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Genomic and molecular characterization of esophageal squamous cell carcinoma.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
The somatic genomic landscape of glioblastoma.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive genomic characterization of head and neck squamous cell carcinomas.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive molecular profiling of lung adenocarcinomaPublicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive genomic characterization of squamous cell lung cancers.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Integrated genomic analyses of ovarian carcinoma.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
The Molecular Taxonomy of Primary Prostate Cancer.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive genomic profiles of small cell lung cancer.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Comprehensive molecular characterization of gastric adenocarcinoma.Publicly available at the cBioPortal (http://www.cbioportal.org) .
-
Integrated genomic characterization of endometrial carcinoma.Publicly available at the cBioPortal (http://www.cbioportal.org) .
Article and author information
Author details
Raffaella Sordella
Funding
National Cancer Institute (NCI P01 CA129243-06)
- Raffaella Sordella
- Marc Ladanyi
- Scott W Lowe
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed in accordance with National Research Council's Guide for the Care and Use of Laboratory Animals. Protocols were approved by the Cold Spring Harbor Laboratory Animal Care and Use Committee (933922-1 Development of mouse models to study human lung cancer - integrated protocols).
Reviewing Editor
- Joaquín M Espinosa, University of Colorado School of Medicine, United States
Publication history
- Received: May 18, 2016
- Accepted: October 17, 2016
- Accepted Manuscript published: October 19, 2016 (version 1)
- Accepted Manuscript updated: October 24, 2016 (version 2)
- Version of Record published: November 2, 2016 (version 3)
- Version of Record updated: February 1, 2017 (version 4)
Copyright
© 2016, Shirole et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,505
- Page views
-
- 822
- Downloads
-
- 29
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions
eLife 5:e17929.
https://doi.org/10.7554/eLife.17929
Further reading
-
- Cancer Biology
- Computational and Systems Biology
Chronic myeloid leukemia (CML) is a blood cancer characterized by dysregulated production of maturing myeloid cells driven by the product of the Philadelphia chromosome, the BCR-ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have proved effective in treating CML, but there is still a cohort of patients who do not respond to TKI therapy even in the absence of mutations in the BCR-ABL1 kinase domain that mediate drug resistance. To discover novel strategies to improve TKI therapy in CML, we developed a nonlinear mathematical model of CML hematopoiesis that incorporates feedback control and lineage branching. Cell–cell interactions were constrained using an automated model selection method together with previous observations and new in vivo data from a chimeric BCR-ABL1 transgenic mouse model of CML. The resulting quantitative model captures the dynamics of normal and CML cells at various stages of the disease and exhibits variable responses to TKI treatment, consistent with those of CML patients. The model predicts that an increase in the proportion of CML stem cells in the bone marrow would decrease the tendency of the disease to respond to TKI therapy, in concordance with clinical data and confirmed experimentally in mice. The model further suggests that, under our assumed similarities between normal and leukemic cells, a key predictor of refractory response to TKI treatment is an increased maximum probability of self-renewal of normal hematopoietic stem cells. We use these insights to develop a clinical prognostic criterion to predict the efficacy of TKI treatment and design strategies to improve treatment response. The model predicts that stimulating the differentiation of leukemic stem cells while applying TKI therapy can significantly improve treatment outcomes.
