Authors: | Senturk, S.; Yao, Z.; Camiolo, M.; Stiles, B.; Rathod, T.; Walsh, A. M.; Nemajerova, A.; Lazzara, M. J.; Altorki, N. K.; Krainer, A.; Moll, U. M.; Lowe, S. W.; Cartegni, L.; Sordella, R. |
Article Title: | P53Ψ 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 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. |
Keywords: | signal transduction; protein expression; unclassified drug; human cell; overall survival; sequence analysis; dna damage; gene targeting; cell function; protein protein interaction; transcription initiation; intron; genetic transcription; protein p53; uvomorulin; transactivation; alternative rna splicing; reactive oxygen species; cell cycle arrest; cellular distribution; gene control; dna binding; tumor suppressor protein; nuclear localization signal; cell invasion; isoprotein; genomic dna; membrane permeability; cell stress; nuclear reprogramming; rna sequence; chromosome 17p; cyclophilin d; mitochondrial permeability; epithelial mesenchymal transition; gain of function mutation; cancer; human; priority journal; article; protein p53 psi |
Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
Volume: | 111 |
Issue: | 32 |
ISSN: | 0027-8424 |
Publisher: | National Academy of Sciences |
Date Published: | 2014-08-12 |
Start Page: | E3287 |
End Page: | E3296 |
Language: | English |
DOI: | 10.1073/pnas.1321640111 |
PROVIDER: | scopus |
PMCID: | PMC4136628 |
PUBMED: | 25074920 |
DOI/URL: | |
Notes: | Cited By (since 1996):1 -- Export Date: 2 September 2014 -- CODEN: PNASA -- Source: Scopus |