Signaling Cascades Activated by UVB in Human Melanocytes Lead to the Increased Expression of Melanocyte Receptors, Endothelin B Receptor and c‐KIT

Abstract

A single exposure of normal human melanocytes (NHMs) to ultraviolet B (UVB) radiation induces a distinct increase in the expression of c-KIT and endothelin B receptor (EDNRB) and upregulates the expression of microphthalmia-associated transcription factor (MITF). In this review, we clarify the signaling mechanisms by which UVB stimulates the expression of MITF in NHMs, thus leading to upregulation of those two important melanogenic receptors. The increased expression of MITF in UVB-exposed NHMs is accompanied by a markedly stimulated and prolonged phosphorylation of p38/CREB. The UVB-stimulated expression of c-KIT and EDNRB could be completely abolished by a p38 inhibitor concomitant with a reduced phosphorylation of CREB and a downregulation of MITF expression. The UVB exposure of NHMs stimulates the phosphorylation of p38 and c-jun N-terminal kinase, but not ERK, followed by the increased phosphorylation of MSK1 and subsequently CREB. Postirradiation treatment with the MSK1 inhibitor H89 significantly downregulates the increased mRNA and protein expression of MITF, EDNRB and c-KIT in UVB-exposed NHMs. Our findings indicate for the first time that the increased expression of MITF that leads to the upregulation of melanocyte-specific proteins in UVB-exposed NHMs is mediated via activation of the p38/MSK1/CREB axis but not the ERK/RSK/CREB axis.

Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

“…Activation of the MC microphthalmia‐associated transcription factor (MITF) in response to secretion of KC‐derived factors (e.g., alpha MC‐stimulating hormone [α–MSH], kit ligand [KITL], endothelin 1 [END‐1]) following UV exposure results in upregulation of melanin‐producing enzymes (including TYRP1, tyrosinase‐related protein 1), and melanin production and secretion (Nguyen & Fisher, ; Serre et al, ). UV exposure also initiates signaling cascades in both KCs and MCs, resulting in secretion of cytokines and chemokines including interleukins (IL1, IL3, IL6, and IL8), interferon (IFN‐γ), granulocyte‐colony stimulating factor (G‐CSF), and tumor necrosis factor α (TNF‐α) (Schwarz & Luger, ; Terazawa & Imokawa, ; Yoshizumi et al, ), which control processes involving cross talk between cells such as the tanning response within the KC:MC unit. Lengthened dendrites and increased dendrite branching in response to UV light increase MC interactions with KCs to facilitate melanin transfer (López et al, ; Weiner et al, ).…”

Mycosporine-like amino acids stimulate hyaluronan secretion by up-regulating hyaluronan synthase 2 via activation of the p38/MSK1/CREB/c-Fos/AP-1 axis

“…During these downstream cascades, further signaling factors such as CREB for MSK1 (59), NFkB (Ser276) for MSK1 (60,61) and c-Fos for CREB (62) are continuously and sequentially activated. Several functional proteins that are highly expressed in UVB-exposed human keratinocytes or human melanocytes, such as cyclooxygenase (COX)2 (50), interleukin (IL)-8 (50), transglutaminase1 (49) (in human keratinocytes), endothelin B receptor (51,63) and stem cell factor receptor c-KIT (in human melanocytes) (63, 64) utilize their characteristic and specific signaling cascades to elicit their increased gene expression.…”

Melanocyte Activation Mechanisms and Rational Therapeutic Treatments of Solar Lentigos

“…We next determined if the increased production of SCF triggers EDNBR expression or its affinity to the EDN ligand in human melanocytes in addition to its stimulatory effect on their proliferation. Western blotting analysis revealed that SCF can stimulate the expression of EDNBR protein in cultured human melanocytes [43]. When the affinity of EDNBR to its ligand was evaluated in cultured human melanocytes using a ligand binding assay, the binding of 125 I-lableled EDN1 to EDNBR was found to be significantly increased two days after incubation with SCF [43].…”

“…Western blotting analysis revealed that SCF can stimulate the expression of EDNBR protein in cultured human melanocytes [43]. When the affinity of EDNBR to its ligand was evaluated in cultured human melanocytes using a ligand binding assay, the binding of 125 I-lableled EDN1 to EDNBR was found to be significantly increased two days after incubation with SCF [43]. Taken together, these findings indicate that SCF expressed in the early phase may enhance the expression of EDNBR, which cause melanocytes to become more sensitive to the later secretion of EDN1.…”

“…Taken together, these findings indicate that SCF expressed in the early phase may enhance the expression of EDNBR, which cause melanocytes to become more sensitive to the later secretion of EDN1. On the other hand, when cultured human melanocytes were treated for 48 h with EDN1 at 10 nM, the ligand binding assay using 125 I-SCF revealed that EDN1 distinctly enhanced the binding affinity of SCF to the c-KIT receptor [43].…”