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).
Copyright
© 2016, Sordella 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
-
- 5,155
- views
-
- 892
- downloads
-
- 51
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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
- Evolutionary Biology
In growing cell populations such as tumours, mutations can serve as markers that allow tracking the past evolution from current samples. The genomic analyses of bulk samples and samples from multiple regions have shed light on the evolutionary forces acting on tumours. However, little is known empirically on the spatio-temporal dynamics of tumour evolution. Here, we leverage published data from resected hepatocellular carcinomas, each with several hundred samples taken in two and three dimensions. Using spatial metrics of evolution, we find that tumour cells grow predominantly uniformly within the tumour volume instead of at the surface. We determine how mutations and cells are dispersed throughout the tumour and how cell death contributes to the overall tumour growth. Our methods shed light on the early evolution of tumours in vivo and can be applied to high-resolution data in the emerging field of spatial biology.
