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

Shirole, N. H., Pal, D., Kastenhuber, E. R., Senturk, S., Boroda, J., Pisterzi, P., Miller, M., Munoz, G., Anderluh, M., Ladanyi, M., Lowe, S. W., Sordella, R. (October 2016) TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions. Elife, 5. ISSN 2050-084X (Electronic)2050-084X (Linking)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/27759562
DOI: 10.7554/eLife.17929

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.

Item Type: Paper
Uncontrolled Keywords: cancer biology cell biology human mouse
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL labs > Sordella lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 19 October 2016
Date Deposited: 27 Oct 2016 18:45
Last Modified: 05 Mar 2018 19:59
PMCID: PMC5092050
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33811

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