Editors' ChoiceCancer

EMT by p53ψ

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Science Signaling  26 Aug 2014:
Vol. 7, Issue 340, pp. ec229
DOI: 10.1126/scisignal.2005830

Loss or aberrant function of the TP53 gene is a common genetic abnormality associated with cancer. One of the primary products of this gene is p53, a transcriptional regulator with key roles in the regulation of the cellular response to genotoxic stress. However, TP53 produces multiple p53 isoforms through alternative splicing and the use of alternative promoters (see Gorrini). When examining the forms of p53 present in tissue-derived immune cells in a mouse lung-injury model and liver-injury model, Senturk et al. identified another p53 variant produced by alternative splicing, which they call p53psi (p53ψ). p53ψ lacks the regions necessary to localize to the nucleus and regulate transcription, and ectopic expression of this variant with or without full-length p53 did not affect expression of a reporter gene or endogenous p53 target genes. Instead, p53ψ was localized to mitochondria. Coimmunoprecipitation and affinity purification analysis indicated that p53ψ interacted with cyclophilin D (CypD), a protein that promotes the opening of the mitochondrial permeability transition pore (mPTP). Ectopic expression of p53ψ stimulated opening of the mPTP, consequently increasing the amount of mitochondrial reactive oxygen species (ROS). Both the opening of the mPTP and the increase in mitochondrial ROS were blocked if CypD was inhibited with cyclosporine A. Increased ROS are associated with the induction of the epithelial-to-mesenchymal transition (EMT) and with increased metastatic competence of cancer cells.

Knockdown of p53ψ in HOP62 cells, a human lung carcinoma cell line with a mutation in TP53 that promotes the production of the transcript for p53ψ, resulted in morphological changes associated with a less mesenchymal phenotype and a more epithelial phenotype, increased the expression of the gene encoding the adhesion protein E-cadherin, and reduced the expression of transcription factors that promote EMT. Ectopic expression of p53ψ in cells that have full-length p53 or are p53-null promoted changes associated with EMT and increased the migratory ability in both a wound-healing assay and a matrix-invasion assay. These EMT-promoting effects of p53ψ were blocked if CypD was inhibited by cyclosporine A or knocked down or if the cells were exposed to ROS scavengers. Analysis of a database of TP53 mutations in cancer samples indicated that many cancers had a mutation in an intron that would favor the production of the p53ψ variant transcript. Analysis of human non–small cell lung cancer (NSCLC) tissue samples revealed that ~20% of the samples had transcripts specific for p53ψ, and patients with p53ψ-positive tumors were more likely to have decreased survival compared with those lacking this isoform. Thus, p53ψ appears to regulate mitochondrial function to promote ROS-mediated EMT and thus cell migratory behavior, which can be prometastatic in cancer cells.

S. Senturk, Z. Yao, M. Camiolo, B. Stiles, T. Rathod, A. M. Walsh, A. Nemajerova, M. J. Lazzara, N. K. Altorki, A. Krainer, U. M. Moll, S. W. Lowe, L. Cartegni, R. Sordella, p53ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like phenotype. Proc. Natl. Acad. Sci. U.S.A. 111, E3287–E3296 (2014). [Abstract] [Full Text]

C. Gorrini, Discovery of a p53 variant that controls metastasis. Proc. Natl. Acad. Sci. U.S.A. 111, 11576–11577 (2014) 10.1073/pnas.1321640111. [Full Text]

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