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P53? is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.


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 p53?. At the molecular level, p53? is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53? 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 p53? 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.

SUBMITTER: Senturk S 

PROVIDER: S-EPMC4136628 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Senturk Serif S   Yao Zhan Z   Camiolo Matthew M   Stiles Brendon B   Rathod Trushar T   Walsh Alice M AM   Nemajerova Alice A   Lazzara Matthew J MJ   Altorki Nasser K NK   Krainer Adrian A   Moll Ute M UM   Lowe Scott W SW   Cartegni Luca L   Sordella Raffaella R  

Proceedings of the National Academy of Sciences of the United States of America 20140729 32


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  ...[more]

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