Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP kinases JNK and p38
Year: 2014
Type: article
Abstract: Melanoma, the deadliest form of skin cancer, is derived from the malignant transformation of melanocytes, epidermal cells that produce the pigment melanin.The main etiological factor for all skin cancers, including melanoma, is exposure to solar ultraviolet (UV) radiation that results in DNA damage.If incorrectly repaired, DNA damage can cause mutations that malignantly transform melanocytes by deregulating critical signaling pathways that control proliferation and survival.Somatic mutations induced by UV cooperate with heritable mutations that increase an individual's susceptibility to melanoma.With the steady rise in the incidence of melanoma over the past 30 years, there is a critical need to better understand the protective mechanisms that reduce the genotoxic effects of solar UV on melanocytes, thus inhibiting melanoma formation.A complex network of paracrine factors in the skin modulates the response of melanocytes to UV.One important keratinocyte-derived paracrine factor is endothelin-1, which has mitogenic, melanogenic and survival effects in human melanocytes.Here, we investigate the role of endothelin-1 and its signaling pathways in reducing the genotoxic effects of UV.We report that endothelin-1 reduces the generation and enhances repair of UV-induced DNA photoproducts in cultured human melanocytes.Reduction in UV-induced DNA damage and apoptosis by endothelin-1 is not due to increased melanin content or proliferation.Treatment with endothelin-1 activates the MAP kinases JNK and p38, and activating transcription factor-2 (ATF-2), and enhances their UV-induced phosphorylation.Inhibition of intracellular calcium mobilization, an important component of the endothelin-1 signaling pathway, markedly abrogates these effects.Activation of both JNK and p38 are required for reducing DNA photoproducts, but only JNK phosphorylation is critical for activation of ATF-2 and inhibition of apoptosis.Activation of viii Marcia Miladinov, Sara Deem and Christy Bailey for their unique contributions to my success.I am very humbled by your generosity and
Authors: von Koschembahr, Anne Meinhardt
Institution: University of Cincinnati
Language: English
Topic: Skin Protection and Aging
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2521594110