p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state
| Autor: | Trushar Rathod, Matthew J. Lazzara, Matthew Camiolo, Zhan Yao, Scott W. Lowe, Alice Nemajerova, Brendon M. Stiles, Adrian R. Krainer, Nasser K. Altorki, Raffaella Sordella, Ute M. Moll, Serif Senturk, Alice M. Walsh, Luca Cartegni |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Gene isoform
Epithelial-Mesenchymal Transition Lung Neoplasms Mutant Biology Lung injury medicine.disease_cause Cyclophilins Mice Carcinoma Non-Small-Cell Lung Cell Line Tumor Commentaries medicine Protein Isoforms Animals Humans Neoplasm Metastasis Gene Mutation Multidisciplinary Alternative splicing Intron CD24 Antigen Lung Injury Cadherins Genes p53 Introns Mitochondria Alternative Splicing Hyaluronan Receptors PNAS Plus RNA splicing Cancer research RNA Splice Sites Tumor Suppressor Protein p53 Reactive Oxygen Species Cyclophilin D |
| Popis: | 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 Psi. 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. |
| Databáze: | OpenAIRE |
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