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1.
FASEB J ; 24(10): 3850-60, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20519635

RESUMO

The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.


Assuntos
Melanócitos/efeitos da radiação , Receptor Tipo 1 de Melanocortina/genética , Raios Ultravioleta , Células Cultivadas , Genótipo , Humanos
2.
Pigment Cell Res ; 19(4): 303-14, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16827749

RESUMO

Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)-induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR-induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR-induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR-induced DNA damage in melanocytes.


Assuntos
Dano ao DNA/efeitos da radiação , Melaninas/fisiologia , Melanócitos/fisiologia , Melanócitos/efeitos da radiação , Receptor Tipo 1 de Melanocortina/fisiologia , Raios Ultravioleta/efeitos adversos , Adulto , Apoptose/efeitos da radiação , Biópsia , Divisão Celular/efeitos da radiação , Células Cultivadas , Reparo do DNA , Humanos , Peróxido de Hidrogênio/metabolismo , Recém-Nascido , Masculino , Melaninas/análise , Melaninas/metabolismo , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/genética , Neoplasias Induzidas por Radiação/genética , Dímeros de Pirimidina/biossíntese , Dímeros de Pirimidina/efeitos da radiação , Receptor Tipo 1 de Melanocortina/metabolismo , Fatores de Risco , Pele/citologia
3.
FASEB J ; 20(9): 1561-3, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16723376

RESUMO

Melanoma is the deadliest form of skin cancer, with no cure for advanced disease. We propose a strategy for melanoma prevention based on using analogs of alpha-melanocyte stimulating hormone (alpha-MSH) that function as melanocortin 1 receptor (MC1R) agonists. Treatment of human melanocytes with alpha-MSH results in stimulation of eumelanin synthesis, reduction of apoptosis that is attributable to reduced hydrogen peroxide generation and enhanced repair of DNA photoproducts. These effects should contribute to genomic stability of human melanocytes, thus preventing their malignant transformation to melanoma. Based on these findings, we synthesized and tested the effects of 3 tetrapeptide alpha-MSH analogs, Ac-His-D-Phe-Arg-Trp-NH2, n-Pentadecanoyl- and 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2, on cultured human melanocytes. The latter two analogs were more potent than the former, or alpha-MSH, in stimulating the activity of tyrosinase, thus melanogenesis, reducing apoptosis and release of hydrogen peroxide and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation (UVR). The above analogs are MC1R agonists, as their effects were abrogated by an analog of agouti signaling protein, the physiological MC1R antagonist, and were absent in melanocytes expressing loss-of-function MC1R. Analogs, such as 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2 with prolonged and reversible effects, can potentially be developed into topical agents to prevent skin photocarcinogenesis, particularly melanoma.


Assuntos
Anticarcinógenos/farmacologia , Dano ao DNA , Melanócitos/efeitos da radiação , Melanoma/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Raios Ultravioleta , alfa-MSH/farmacologia , Humanos , Melanócitos/citologia , Melanócitos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , alfa-MSH/química
4.
Pigment Cell Res ; 16(5): 434-47, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12950718

RESUMO

Solar ultraviolet radiation (UV) is a major environmental factor that dramatically alters the homeostasis of the skin as an organ by affecting the survival, proliferation and differentiation of various cutaneous cell types. The effects of UV on the skin include direct damage to DNA, apoptosis, growth arrest, and stimulation of melanogenesis. Long-term effects of UV include photoaging and photocarcinogenesis. Epidermal melanocytes synthesize two main types of melanin: eumelanin and pheomelanin. Melanin, particularly eumelanin, represents the major photoprotective mechanism in the skin. Melanin limits the extent of UV penetration through the epidermal layers, and scavenges reactive oxygen radicals that may lead to oxidative DNA damage. The extent of UV-induced DNA damage and the incidence of skin cancer are inversely correlated with total melanin content of the skin. Given the importance of the melanocyte in guarding against the adverse effects of UV and the fact that the melanocyte has a low self-renewal capacity, it is critical to maintain its survival and genomic integrity in order to prevent malignant transformation to melanoma, the most fatal form of skin cancer. Melanocyte transformation to melanoma involves the activation of certain oncogenes and the inactivation of specific tumor suppressor genes. This review summarizes the current state of knowledge about the role of melanin and the melanocyte in photoprotection, the responses of melanocytes to UV, the signaling pathways that mediate the biological effects of UV on melanocytes, and the most common genetic alterations that lead to melanoma.


Assuntos
Melanócitos/efeitos da radiação , Pele/efeitos da radiação , Luz Solar/efeitos adversos , Animais , Dano ao DNA , Reparo do DNA , Humanos , Melaninas/metabolismo , Melanócitos/metabolismo , Melanoma/etiologia , Modelos Biológicos , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/prevenção & controle , Fotobiologia , Proteção Radiológica , Raios Ultravioleta/efeitos adversos
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