Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38

Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38

Bibliographic Details
Main Author: von Koschembahr, Anne M.
Language:English
Published: University of Cincinnati / OhioLINK 2014
Subjects:
Cellular Biology
endothelin-1
human melanocytes
ultraviolet radiation
JNK
p38
DNA damage
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14189094212021-08-03T06:28:37Z Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38 von Koschembahr, Anne M. Cellular Biology endothelin-1 human melanocytes ultraviolet radiation JNK p38 DNA damage 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 ATF-2 is not sufficient for reducing UV-induced DNA damage by endothelin-1. We propose that endothelin-1 restores genomic stability of human melanocytes by reducing the genotoxic effects of UV through its ability to activate the stress-activated MAP kinase signaling pathways (specifically JNK and p38), thus preventing melanoma. Future studies will further delineate the activation of DNA repair pathways by endothelin-1. Understanding the mechanisms by which endothelin-1 counteracts the photodamaging effects of UV might identify new targets for melanoma prevention. 2014 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Cellular Biology
endothelin-1
human melanocytes
ultraviolet radiation
JNK
p38
DNA damage
spellingShingle Cellular Biology
endothelin-1
human melanocytes
ultraviolet radiation
JNK
p38
DNA damage
von Koschembahr, Anne M.
Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38
author von Koschembahr, Anne M.
author_facet von Koschembahr, Anne M.
author_sort von Koschembahr, Anne M.
title Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38
title_short Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38
title_full Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38
title_fullStr Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38
title_full_unstemmed Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38
title_sort endothelin-1 protects human melanocytes from the photodamaging effects of ultraviolet radiation by activating the map kinases jnk and p38
publisher University of Cincinnati / OhioLINK
publishDate 2014
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421
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