p53Psi is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state

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. (July 2014) p53Psi is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state. Proceedings of the National Academy of Sciences of the United States of America, 111 (32). E3287-E3296. ISSN 0027-8424

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URL: http://www.ncbi.nlm.nih.gov/pubmed/25074920
DOI: 10.1073/pnas.1321640111

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 p53Psi. At the molecular level, p53Psi is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Psi 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 p53Psi 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.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
diseases & disorders > cancer > metastasis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Krainer lab
CSHL labs > Sordella lab
CSHL Cancer Center Shared Resources > Flow Cytometry Service
Depositing User: Matt Covey
Date: 29 July 2014
Date Deposited: 08 Aug 2014 15:20
Last Modified: 20 Dec 2017 21:15
PMCID: PMC4136628
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30675

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