Unknown

Dataset Information

0

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


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 the 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.

SUBMITTER: Shirole NH 

PROVIDER: S-EPMC5092050 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

<i>TP53</i> exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions.

Shirole Nitin H NH   Pal Debjani D   Kastenhuber Edward R ER   Senturk Serif S   Boroda Joseph J   Pisterzi Paola P   Miller Madison M   Munoz Gustavo G   Anderluh Marko M   Ladanyi Marc M   Lowe Scott W SW   Sordella Raffaella R  

eLife 20161019


<i>TP53</i> truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that <i>TP53</i> 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 ca  ...[more]

Similar Datasets

| S-EPMC5501868 | biostudies-literature
| S-EPMC2663021 | biostudies-literature
| S-EPMC5589071 | biostudies-literature
| S-EPMC3096962 | biostudies-literature
| S-EPMC7384961 | biostudies-literature
| S-EPMC3901069 | biostudies-literature
| S-EPMC6855950 | biostudies-literature
| S-EPMC4308813 | biostudies-literature
| S-EPMC8991692 | biostudies-literature
| S-EPMC10709652 | biostudies-literature