Mitogen- and Ultraviolet-B-Induced Signaling Pathways in Normal Human Melanocytes

Tada, Akihiro; Pereira, Elizabeth; Beitner‐Johnson, Dana; Kavanagh, Renny; Abdel‐Malek, Zalfa

doi:10.1046/j.0022-202x.2001.01694.x

Cited by 88 publications

(93 citation statements)

References 43 publications

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“…Treatment of human melanocytes with ET-1 activates the same MAP kinase pathway and phosphorylates CREB on Ser 133 ; these effects are enhanced in the concomitant presence of a-MSH (47,48). In human melanocytes, CREB phosphorylation is also induced by UV, in part via activation of the MAP kinase p38 (48).…”

Section: Discussionmentioning

confidence: 94%

α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes

Kadekaro¹,

Kavanagh²,

Kanto³

et al. 2005

Cancer Research

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241

292

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UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors A-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that A-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of A-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with A-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with A-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis. (Cancer Res 2005; 65(10): 4292-9)

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Section: Discussionmentioning

confidence: 94%

α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes

Kadekaro¹,

Kavanagh²,

Kanto³

et al. 2005

Cancer Research

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241

292

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“…Benign nevi are located in the skin surface and are thoroughly exposed to UV-radiation and it may be speculated, therefore, that the profound JNK activation has a protective role restricting uncontrolled growth or survival of the nevus cells. Although p38 has been shown to also be activated by UV-radiation, 37 the low degree of activation in benign nevi suggests a less obvious role for this kinase in early stages of melanogenesis. In support of the differential activation of JNK and p38 in benign nevi, Vicent et al 17 recently observed activation of JNK but not p38 in normal cells of the lung.…”

Section: Discussionmentioning

confidence: 99%

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

2006

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Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P ¼ 0.017) and shorter disease-free survival (P ¼ 0.003) as well as with markers of cell proliferation (cyclin A (P ¼ 0.017) and p21 (P ¼ 0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P ¼ 0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK1/2 (P ¼ 0.005) and p-p38 (P ¼ 0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (Po0.0005) and p-Akt (P ¼ 0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P ¼ 0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.

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“…Cross-talk between the NR4A Nuclear Receptor and MC1R Signaling Cascades in B16 Melanoma Cells-Although MC1R signaling functions primarily via the stimulation of adenylate cyclase resulting in the production of cAMP, emerging evidence suggests that a number of other signaling cascades are also activated by MC1R in melanocytic cells (10,41,47,48). Moreover, the NR4A subgroup has been shown to be targets of cAMP signaling in a number of cell types (25,26).…”

Section: Induction Of Nr4a Gene Expression By Mc1r Signaling In B16mentioning

confidence: 99%

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

Smith¹,

Luk²,

Newton

et al. 2008

Journal of Biological Chemistry

107

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The melanocortin-1 receptor (MCIR) is a G-protein-coupled receptor expressed primarily in melanocytes and is known to play a pivotal role in the regulation of pigmentation in mammals. In humans MC1R has been found to be highly polymorphic with several functional variants associated with the phenotype of red hair color and fair skin, cutaneous UV sensitivity, and increased risk of developing melanoma and non-melanoma skin cancer. Recent evidence suggests that MC1R plays a photo-protective role in melanocytes in response to UV irradiation. Relatively few genetic targets of MC1R signaling have been identified independent of the pigmentation pathway. Here we show that MC1R signaling in B16 mouse melanoma cells and primary human melanocytes rapidly, and transiently, induces the transcription of the NR4A subfamily of orphan nuclear receptors. Furthermore, primary human melanocytes harboring homozygous RHC variant MC1R alleles exhibited an impaired induction of NR4A genes in response to the potent MC1R agonist (Nle4,D-Phe7)-␣-melanocyte-stimulating hormone. Using small interference RNA-mediated attenuation of NR4A1 and NR4A2 expression in melanocytes, the ability to remove cyclobutane pyrimidine dimers following UV irradiation appeared to be impaired in the context of MC1R signaling. These data identify the NR4A receptor family as potential mediators of an MC1R-coordinated DNA damage response to UV exposure in melanocytic cells.It has long been recognized that individuals with fair skin and poor tanning ability have an increased incidence of melanoma and non-melanoma skin cancer (1-3). Cutaneous pigmentation in humans is the result of melanin synthesis by epidermal melanocytes within specialized organelles termed melanosomes, which are transferred to surrounding keratinocytes (4).Human pigmentation is a polygenic trait with Ͼ60 genetic loci identified so far (5, 6). Efforts over the last decade to understand the genetic basis of human pigmentary traits have revealed the melanocortin-1 receptor (MC1R) 5 as a key determinant of the wide phenotypic diversity in mammals (7-9). MC1R is a seven-transmembrane G-protein-coupled receptor that has been found to be highly polymorphic in Caucasian individuals, with a number of functional variants strongly associating with a phenotype of red hair, fair skin, and poor tanning ability often referred to as the Red Hair Color (RHC) phenotype (7). MC1R preferentially binds the pro-opiomelanocortin-derived peptides ␣-melanocyte-stimulating hormone (␣-MSH) and adrenocorticotropic hormone, which leads to an elevation in intracellular cAMP levels (10). RHC variant MC1Rs have been demonstrated to elicit weak cAMP responses as a result of reduced receptor coupling (2, 11-13) or abnormal receptor localization (2, 12-15). Molecular analysis has revealed that MC1R signaling modulates the expression and function of the microphthalmia-associated transcription factor, a key regulator of pigmentation genes, suggesting that this pathway underlies MC1R coordination of melanogenesis (16). Accumulating ...

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Mitogen- and Ultraviolet-B-Induced Signaling Pathways in Normal Human Melanocytes

Cited by 88 publications

References 43 publications

α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes

α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

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