p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response.
Nat Commun
; 9(1): 1021, 2018 03 09.
Article
em En
| MEDLINE
| ID: mdl-29523849
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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
/
Proteínas de Transporte
/
Queratinócitos
/
Transativadores
/
Estresse Oxidativo
/
Proliferação de Células
/
Carcinoma de Células Escamosas do Esôfago
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2018
Tipo de documento:
Article