TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions

Abstract
Data availability
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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

The following previously published data sets were used

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Article and author information

Author details

Raffaella Sordella

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

For correspondence
sordella@cshl.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9745-1227
Nitin H Shirole

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Debjani Pal

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

Competing interests
The authors declare that no competing interests exist.
Edward R Kastenhuber

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Serif Senturk

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

Competing interests
The authors declare that no competing interests exist.
Joseph Boroda

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

Competing interests
The authors declare that no competing interests exist.
Paola Pisterzi

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

Competing interests
The authors declare that no competing interests exist.
Madison Miller

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

Competing interests
The authors declare that no competing interests exist.
Gustavo Munoz

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Marko Anderluh

Department of Medicinal Chemistry, University of Ljubljana, Ljubljana, Slovenia

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The authors declare that no competing interests exist.
Marc Ladanyi

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Scott W Lowe

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.

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

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.