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

Serif Senturk, Zhan Yao, Matthew Camiolo, Brendon Stiles, Trushar Rathod, Alice M. Walsh, Alice Nemajerova, Matthew J. Lazzara, Nasser K. Altorki, Adrian Krainer, Ute M. Moll, Scott W. Lowe, Luca Cartegni, Raffaella Sordella

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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-offunction 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 themitochondrial 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.

Original languageEnglish (US)
Pages (from-to)E3287-E3296
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number32
DOIs
StatePublished - Aug 12 2014
Externally publishedYes

Keywords

  • Cancer
  • Reactive oxygen species

ASJC Scopus subject areas

  • General

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