P53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state Academic Article uri icon

Overview

MeSH Major

  • Genes, p53
  • Neoplasm Metastasis
  • Tumor Suppressor Protein p53

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.

publication date

  • August 12, 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4136628

Digital Object Identifier (DOI)

  • 10.1073/pnas.1321640111

PubMed ID

  • 25074920

Additional Document Info

start page

  • E3287

end page

  • 96

volume

  • 111

number

  • 32