Endothelin‐1 is a transcriptional target of p53 in epidermal keratinocytes and regulates ultraviolet‐induced melanocyte homeostasis

Abstract

Summary Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of EDN1 in murine epidermis (EDN1ep−/−) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage and apoptosis after UVB irradiation. Expression of other keratinocyte derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV induced melanocyte activation and recapitulated the phenotype seen in EDN1ep−/− mice. Altogether, present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV induced melanocyte homeostasis in vivo.

Nrf2 in keratinocytes modulates UVB-induced DNA damage and apoptosis in melanocytes through MAPK signaling

“…They are in agreement with previous studies indicating protective effects of KC against UVB-induced pathologies including DNA damage, apoptosis and melanogenesis in MC [30–34]. Proposed mechanisms responsible for the role of neighbouring KC in mediating UVB-stimulated physiological responses of MC in association with inhibition of oxidative stress would likely involve the paracrine effects of factors produced by epidermal KC [7,9,10,13,35,36]. We therefore addressed the role of Nrf2 in modulation of KC’s paracrine effects on UVB-mediated MC damage.…”

Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention

“…2). Both a-MSH and endothelin-1 are synthesized by human keratinocytes, and their synthesis is augmented upon UV exposure [20,49,50,99]. In mice with targeted deletion of the endothelin-1 gene in keratinocytes, the number of melanocytes was reduced as well their DNA repair capacity, lending in vivo evidence for the significance of endothelin-1 in maintaining the homeostasis of melanocytes [49].…”

“…Both a-MSH and endothelin-1 are synthesized by human keratinocytes, and their synthesis is augmented upon UV exposure [20,49,50,99]. In mice with targeted deletion of the endothelin-1 gene in keratinocytes, the number of melanocytes was reduced as well their DNA repair capacity, lending in vivo evidence for the significance of endothelin-1 in maintaining the homeostasis of melanocytes [49]. These two factors are known to interact synergistically to stimulate melanocyte proliferation and melanogenesis, and to maintain melanocyte survival by inhibiting UV-induced apoptosis and enhancing DNA repair [56,117,118].…”

Loss of Keratinocytic RXRα Combined with Activated CDK4 or Oncogenic NRAS Generates UVB-Induced Melanomas via Loss of p53 and PTEN in the Tumor Microenvironment

“…These Rxrα ep−/− mice show increased melanocyte proliferation and defective DNA damage repair following acute ultraviolet-B (UVB) irradiation [5], and have increased melanocytic tumor formation resulting from chemical carcinogenesis [6,9]. Expression of several mitogenic factors are upregulated in keratinocytes lacking RXRα, including Endothelin-1 (EDN1), Stem Cell Factor (SCF), Microphthalmia-associated Transcription Factor (MITF), and Hepatocyte Growth Factor (HGF) [5,6,10], which stimulate melanocyte activation/proliferation in vitro [5,10]. We also found that combining epidermis-specific RXRα knockout with an activating Cyclin-Dependent Kinase 4 (CDK4) mutation (R24C) in a bigenic mouse model further enhanced chemical carcinogen-induced melanomagenesis, suggesting a cooperative effect between RXRα signaling and a key oncogenic driver [6].…”