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p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response.

Arcidiacono, P; Webb, CM; Brooke, MA; Zhou, H; Delaney, PJ; Ng, K-E; Blaydon, DC; Tinker, A; Kelsell, DP; Chikh, A (2018) p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response. Nat Commun, 9 (1). p. 1021. ISSN 2041-1723 https://doi.org/10.1038/s41467-018-03470-y
SGUL Authors: Chikh, Anissa

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Abstract

Hyperproliferative keratinocytes induced by trauma, hyperkeratosis and/or inflammation display molecular signatures similar to those of palmoplantar epidermis. Inherited gain-of-function mutations in RHBDF2 (encoding iRHOM2) are associated with a hyperproliferative palmoplantar keratoderma and squamous oesophageal cancer syndrome (termed TOC). In contrast, genetic ablation of rhbdf2 in mice leads to a thinning of the mammalian footpad, and reduces keratinocyte hyperproliferation and migration. Here, we report that iRHOM2 is a novel target gene of p63 and that both p63 and iRHOM2 differentially regulate cellular stress-associated signalling pathways in normal and hyperproliferative keratinocytes. We demonstrate that p63-iRHOM2 regulates cell survival and response to oxidative stress via modulation of SURVIVIN and Cytoglobin, respectively. Furthermore, the antioxidant compound Sulforaphane downregulates p63-iRHOM2 expression, leading to reduced proliferation, inflammation, survival and ROS production. These findings elucidate a novel p63-associated pathway that identifies iRHOM2 modulation as a potential therapeutic target to treat hyperproliferative skin disease and neoplasia.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2018
Keywords: Animals, Apoptosis, Carrier Proteins, Cell Line, Cell Proliferation, Cell Survival, Cytoglobin, Esophageal Squamous Cell Carcinoma, Female, HEK293 Cells, Humans, Isothiocyanates, Keratinocytes, Mice, Mice, Knockout, Oxidative Stress, Phosphoproteins, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Skin Diseases, Survivin, Trans-Activators, Cell Line, Keratinocytes, Animals, Mice, Knockout, Humans, Mice, Skin Diseases, Reactive Oxygen Species, Isothiocyanates, Carrier Proteins, Trans-Activators, Phosphoproteins, RNA, Small Interfering, Apoptosis, Cell Proliferation, Cell Survival, RNA Interference, Oxidative Stress, Female, HEK293 Cells, Survivin, Esophageal Squamous Cell Carcinoma, Cytoglobin, MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
Dates:
DateEvent
9 March 2018Published
14 February 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/L010402/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG/13/19/30568British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
C7570/A19107Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
PubMed ID: 29523849
Web of Science ID: WOS:000427027200009
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111985
Publisher's version: https://doi.org/10.1038/s41467-018-03470-y

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