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p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.

Matin, RN; Chikh, A; Chong, SLP; Mesher, D; Graf, M; Sanza', P; Senatore, V; Scatolini, M; Moretti, F; Leigh, IM; et al. Matin, RN; Chikh, A; Chong, SLP; Mesher, D; Graf, M; Sanza', P; Senatore, V; Scatolini, M; Moretti, F; Leigh, IM; Proby, CM; Costanzo, A; Chiorino, G; Cerio, R; Harwood, CA; Bergamaschi, D (2013) p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis. J Exp Med, 210 (3). pp. 581-603. ISSN 1540-9538 https://doi.org/10.1084/jem.20121439
SGUL Authors: Chikh, Anissa

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Abstract

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.

Item Type: Article
Additional Information: © 2013 Matin et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Keywords: Adult, Aged, Aged, 80 and over, Apoptosis, Cell Line, Tumor, DNA Damage, Drug Resistance, Neoplasm, Female, Flow Cytometry, Humans, Male, Melanoma, Membrane Proteins, Middle Aged, Mitochondria, Prognosis, Protein Transport, Proto-Oncogene Proteins c-mdm2, Skin Neoplasms, Tumor Suppressor Protein p53, Cell Line, Tumor, Mitochondria, Humans, Melanoma, Skin Neoplasms, DNA Damage, Membrane Proteins, Prognosis, Flow Cytometry, Apoptosis, Protein Transport, Drug Resistance, Neoplasm, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2, 11 Medical and Health Sciences, Immunology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: J Exp Med
ISSN: 1540-9538
Language: eng
Dates:
DateEvent
11 March 2013Published
18 January 2013Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-Share Alike 3.0
Projects:
Project IDFunderFunder ID
13044Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
G0600450Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 23420876
Web of Science ID: WOS:000315997000012
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111986
Publisher's version: https://doi.org/10.1084/jem.20121439

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