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Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):E3287-96. doi: 10.1073/pnas.1321640111. Epub 2014 Jul 29.

p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.

Author information

1
Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724;
2
Department of Cardiothoracic Surgery, Weill Cornell Medical Center, New York, NY 10065;
3
Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
4
Bioengineering Department, University of Pennsylvania, Philadelphia, PA 19104; and.
5
Department of Pathology, Stony Brook University, Stony Brook, NY 11794.
6
Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724; sordella@cshl.edu.

Abstract

Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.

KEYWORDS:

cancer; reactive oxygen species

Comment in

PMID:
25074920
PMCID:
PMC4136628
DOI:
10.1073/pnas.1321640111
[Indexed for MEDLINE]
Free PMC Article
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