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

von Koschembahr, Anne M.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
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.
Zalfa Abdelmalek, Ph.D. (Committee Chair)
Chunying Du, Ph.D. (Committee Member)
Sohaib Khan, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
David Plas, Ph.D. (Committee Member)
164 p.
Cellular Biology
endothelin-1; human melanocytes; ultraviolet radiation; JNK; p38; DNA damage

Recommended Citations

Citations

  • von Koschembahr, A. M. (2014). Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38 [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421

    APA Style (7th edition)

  • von Koschembahr, Anne. Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421.

    MLA Style (8th edition)

  • von Koschembahr, Anne. "Endothelin-1 Protects Human Melanocytes from the Photodamaging Effects of Ultraviolet Radiation by Activating the MAP Kinases JNK and p38." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1418909421

    Chicago Manual of Style (17th edition)

ucin1418909421
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This open access ETD is published by University of Cincinnati and OhioLINK.