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.
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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, 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.
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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
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- 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.
