The hallmark of sun exposure is the tanning response, the outcome of increased melanin synthesis by epidermal melanocytes and enhanced transfer of melanosomes from melanocytes to keratinocytes. Constitutive pigmentation determines the extent of the melanogenic response to sun exposure, and the poor tanning response of individuals with skin type I or II is associated with increased risk for skin cancer. Ultraviolet light has direct genotoxic effects, as well as indirect cellular effects which are mediated by increased synthesis of various paracrine/autocrine epidermal factors. Factors known to regulate pigmentation are alpha-melanotropin (alpha-MSH) and adrenocorticotropic hormone (ACTH) which are mitogenic and melanogenic for human melanocytes, and endothelin-1 which is a mitogen for, and a modulator of melanogenesis in, these cells. Recently, it was reported that variants of the melanocortin-1 receptor gene are expressed by skin type I and II individuals, suggesting a role for this receptor in determining the pigmentary response to sun exposure. alpha-Melanotropin mediates its effects primarily by activating the cAMP-dependent pathway. We found that activation of the cAMP pathway in human melanocytes is pivotal for the melanogenic response to ultraviolet light. Endothelin-1 activates multiple signaling pathways, including cAMP, intracellular Ca+2, protein kinase C, and tyrosine kinase-dependent pathways. Also, endothelin-1 seems to be important for the melanogenic response of human melanocytes to ultraviolet light. Endothelin-1 stimulates human melanocyte proliferation in a dose-dependent manner, but has a biphasic effect on the activity and protein level of tyrosinase: a stimulatory effect at subnanomolar concentrations, and an inhibitory effect at higher concentrations. This modulation of tyrosinase correlates with the extent of mobilization of intracellular Ca+2 by different concentrations of endothelin-1, a mechanism that might be significant in the physiologic regulation of melanogenesis. Endothelin-1 and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation and addictively to modulate melanogenesis. We hypothesize that the response of normal human melanocytes to ultraviolet light is regulated by the crosstalk of different signaling pathways that are activated by endothelin-1 and alpha-melanotropin. Based on this, we propose to elucidate the significance of the melanocortin-1 receptor, the role of endothelin-1, and the participation of the cAMP and Ca+2-dependent pathways in the regulation of human melanocyte proliferation and melanogenesis. particularly in response to ultraviolet light.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009110-02
Application #
2900433
Study Section
Radiation Study Section (RAD)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Dermatology
Type
Schools of Medicine
DUNS #
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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