In human skin, epidermal melanocytes play a crucial role in photoprotection mainly due to their ability to synthesize melanin. Melanocytes have an extremely low proliferative capacity, thus their survival in the epidermis is crucial for cutaneous photoprotection. However, it is becoming clear that the risk for skin cancer is not simply determined by melanin content in the skin, but rather by the ability of the metanocyte to maintain genomic stability in the face of exposure to ultraviolet radiation, to prevent malignant transformation into melanoma. Endothelin-1 (ET-1) and alpha-melanocyte stimulating hormone (alpha-MSH) are two epidermal factors whose synthesis is stimulated by UV exposure. Both factors enable human melanocytes to overcome UV-induced G1 arrest and stimulate melanogenesis. Recently, we demonstrated that ET-1 and apha-MSH increase the survival of UV-irradiated melanocytes by inhibiting apoptosis. We found that cultured human melanocytes that express loss-of-function mutations in the melanocortin 1 receptor, the receptor for alpha-MSH, have increased susceptibility to killing by UVR. We attribute this increased sensitivity to UV exposure to extensive DNA damage that overwhelms the repair capacity of those cells, and to inability to fully activate survival pathways. These mutations have been associated with poor tanning ability, and increased risk for melanoma and non-melanoma skin cancers, independently of skin or hair color. We hypothesize that ET- 1 and alpha-MSH promote human melanocyte survival by inhibiting apoptosis and reducing the extent of UVB-induced DNA damage. We propose to investigate the ability of ET-1 and/or a-MSH to limit the extent of UVB-induced DNA damage and/or to enhance the rate of DNA repair. We will also determine the capacity of ET-1 and alpha-MSH to activate the Akt/PKBdependent survival pathway. Activated Akt/PKB is known to inhibit apoptosis by phosphorylating and inactivating its substrates Bad and caspase 9, and by activating NFkB and CREB. Additionally, we plan to elucidate whether the survival effects of ET-1 and/or alpha-MSH involve activation of the transcription factor Mitf, which upregulates Bcl2 expression, by modulating the activities of ERK1/2, p38 and JNK/SAPK, and CREB in UVB-irradiated melanocytes. Determining the differences in the ability of melanocytes from different pigmentary phenotypes to respond to survival factors is significant for assessing the magnitude of the cytotoxic and genotoxic effects of UVR in the skin. Also, assessing the differential sensitivity to the survival effects of a-MSH and ET-1 can be used as a reliable marker for determining individual risk to skin cancer, particularly melanoma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009110-06
Application #
6780438
Study Section
Radiation Study Section (RAD)
Program Officer
Humble, Michael C
Project Start
1998-04-01
Project End
2008-03-31
Budget Start
2004-04-23
Budget End
2005-03-31
Support Year
6
Fiscal Year
2004
Total Cost
$328,106
Indirect Cost
Name
University of Cincinnati
Department
Dermatology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
García-Borrón, Jose C; Abdel-Malek, Zalfa; Jiménez-Cervantes, Celia (2014) MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation. Pigment Cell Melanoma Res 27:699-720
Swope, Viki; Alexander, Christina; Starner, Renny et al. (2014) Significance of the melanocortin 1 receptor in the DNA damage response of human melanocytes to ultraviolet radiation. Pigment Cell Melanoma Res 27:601-10
Denat, Laurence; Kadekaro, Ana L; Marrot, Laurent et al. (2014) Melanocytes as instigators and victims of oxidative stress. J Invest Dermatol 134:1512-1518
Kadekaro, Ana Luisa; Chen, Juping; Yang, Jennifer et al. (2012) Alpha-melanocyte-stimulating hormone suppresses oxidative stress through a p53-mediated signaling pathway in human melanocytes. Mol Cancer Res 10:778-86
Swope, Viki B; Jameson, Joshua A; McFarland, Kevin L et al. (2012) Defining MC1R regulation in human melanocytes by its agonist ?-melanocortin and antagonists agouti signaling protein and ?-defensin 3. J Invest Dermatol 132:2255-62
Herraiz, Cecilia; Journe, Fabrice; Abdel-Malek, Zalfa et al. (2011) Signaling from the human melanocortin 1 receptor to ERK1 and ERK2 mitogen-activated protein kinases involves transactivation of cKIT. Mol Endocrinol 25:138-56
Starner, Renny J; McClelland, Lindy; Abdel-Malek, Zalfa et al. (2010) PGE(2) is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation. Exp Dermatol 19:682-4
Abdel-Malek, Zalfa A (2010) Development of ?-melanocortin analogs for melanoma prevention and targeting. Adv Exp Med Biol 681:126-32
Kadekaro, Ana Luisa; Leachman, Sancy; Kavanagh, Renny J et al. (2010) Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J 24:3850-60
Abdel-Malek, Zalfa A; Kadekaro, Ana Luisa; Swope, Viki B (2010) Stepping up melanocytes to the challenge of UV exposure. Pigment Cell Melanoma Res 23:171-86

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