Endothelin-1 enhances the melanogenesis via MITF-GPNMB pathway

Abstract

Endothelin-1 (ET-1) plays an indispensable role in epidermal pigmentation in hyperpigmentary disorders due to a central role in melanogenesis. Nevertheless, precise mechanism involved in ET-1-induced hyperpigmentation is still undefined. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB) is a key element in melanosome formation. Therefore, we speculated that GPNMB was correlated with ET-1-induced pigmentation. After culturing with ET-1, melanin synthesis was significantly up-regulated, accompanying with increased expression of GPNMB and microphthalmia-associated transcription factor (MITF). Total number of melanosomes and melanin synthesis were sharply reduced via GPNMB-siRNA transfection, indicating ET-1-induced pigmentation by GPNMB-dependent manner. Furthermore, MITFsiRNA transfection strikingly inhibited GPNMB expression and the melanogenesis, and this suppression failed to be alleviated by ET-1 stimulation. All of these results demonstrated that ET-1 can trigger melanogenesis via the MITF-regulated GPNMB pathway. Taken together, these findings will provide a new explanation of how ET-1 induces hyperpigmentation, and possibly supply a new strategy for cosmetic studies. [BMB Reports 2013; 46(7): 364-369]

MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB

“…Glycoprotein (transmembrane) Nmb (GPNMB) is a normal constituent of melanosomes and is required for UVB or endothelin-1 stimulated melanogenesis (13, 14). Our data demonstrate that GPNMB levels are induced in BRAF mutant melanoma cells in response to clinically indicated BRAF and MEK inhibitors; this is in agreement with previous studies that employed experimental MAPK pathway inhibitors (30).…”

“…GPNMB is a heavily glycosylated transmembrane protein that localizes to late stage melanosomes, lysosomes and the cell surface. Moreover, GPNMB is required for melanin production in melanocytes (13, 14). In breast cancer, GPNMB promotes breast tumor migration, invasion and metastasis (15–17).…”

GPNMB ameliorates mutant TDP‐43‐induced motor neuron cell death

“…Therefore, GPNMB likely has some relationship with TDP‐43 in ALS patients. GPNMB is known to bind to certain types of proteins (Li et al, ; Shikano et al, ; Zhang et al, ). Previously, we reported that GPNMB has protective effects in theSOD1 (G93A) mouse model of ALS, and in an in vitro model of ALS (Nagahara et al, ; Nagahara et al, ; Tanaka et al, ).…”

Paracrine regulation of melanogenesis

“…Endothelins (EDNs) are secreted mainly from keratinocytes and bind to EDN receptors on melanocytes to regulate melanogenesis . In response to UV, expression of EDNs is highly elevated to enhance the signalling cascades, among which the EDN1–EDN receptor type B (EDNRB) pathway is considered to play significant role in UVB‐induced pigmentation by modulating MITF phosphorylation in normal human melanocytes …”

“…36 In response to UV, expression of EDNs is highly elevated to enhance the signalling cascades, among which the EDN1-EDN receptor type B (EDNRB) pathway is considered to play significant role in UVB-induced pigmentation by modulating MITF phosphorylation in normal human melanocytes. 12,37,38 Nitric oxide (NO), a kind of diffusible free radical gas synthesized by the enzyme NO synthase, is considered to be a main intracellular and intercellular messenger molecule in different cells and tissues. 39 The stimulatory melanogenic effect of paracrine factors produced by keratinocytes in response to UV has been reported to be markedly blocked by NO scavengers in normal human melanocyte and keratinocyte cocultures, suggesting an important role of NO in UV-induced melanogenesis.…”