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Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation.

ABSTRACT: Rationale: Microphthalmia-associated transcription factor M (MITF-M) plays important roles in the pigment production, differentiation and survival of melanocytes. Stem cell factor (SCF) and its receptor KIT stimulate MITF-M activity via phosphorylation at the post-translation level. However, the phosphorylation shortens half-life of MITF-M protein over the course of minutes. Here, we investigated novel hypotheses of (i) whether SCF/KIT can regulate MITF-M activity through gene expression as the alternative process, and (ii) whether chemical inhibition of KIT activity can mitigate the acquired pigmentation in skin by targeting the expression of MITF-M. Methods: We employed melanocyte cultures in vitro and pigmented skin samples in vivo, and applied immunoblotting, RT-PCR, siRNA-based gene knockdown and confocal microscopy. Results: The protein and mRNA levels of MITF-M in epidermal melanocytes and the promoter activity of MITF-M in B16-F0 melanoma cells demonstrated that SCF/KIT could trigger the expression of MITF-M de novo, following the phosphorylation-dependent proteolysis of pre-existing MITF-M protein. SCF/KIT regulated the transcription abilities of cAMP-responsive element-binding protein (CREB), CREB-regulated co-activator 1 (CRTC1) and SRY-related HMG-box 10 (SOX10) but not ?-catenin at the MITF-M promoter. Meanwhile, chemical inhibition of KIT activity abolished SCF-induced melanin production in epidermal melanocyte cultures, as well as protected the skin from UV-B-induced hyperpigmentation in HRM2 mice or brownish guinea pigs, in which it down-regulated the expression of MITF-M de novo at the promoter level. Conclusion: We propose the targeting of SCF/KIT-inducible MITF-M expression as a strategy in the therapeutics for acquired pigmentary disorders.

SUBMITTER: Yun CY

PROVIDER: S-EPMC6929618 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation.

Yun Cheong-Yong CY Roh Eunmiri E Kim Song-Hee SH Han Jinhe J Lee Jiyeon J Jung Da-Eun DE Kim Ga Hyeon GH Jung Sang-Hun SH Cho Won-Jea WJ Han Sang-Bae SB Kim Youngsoo Y

Theranostics 20200101 1

<b>Rationale:</b> Microphthalmia-associated transcription factor M (MITF-M) plays important roles in the pigment production, differentiation and survival of melanocytes. Stem cell factor (SCF) and its receptor KIT stimulate MITF-M activity via phosphorylation at the post-translation level. However, the phosphorylation shortens half-life of MITF-M protein over the course of minutes. Here, we investigated novel hypotheses of (i) whether SCF/KIT can regulate MITF-M activity through gene expression ...[more]

PMID: 31903124

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Project description:Background: Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin pigmentation through microphthalmia-associated transcription factor M (MITF-M). Toll-like receptor 4 (TLR4), a receptor of endotoxin lipopolysaccharide (LPS), is distributed in immune and other cell types including melanocytes where LPS/TLR4 activate transcriptional activity of nuclear factor (NF)-κB to express cytokines in innate immunity. LPS/TLR4 also up-regulate MITF-M-target melanogenic genes in melanocytes. Here, we propose a molecular target of antimelanogenic activity through elucidating inhibitory mechanism on α-MSH-induced melanogenic programs by benzimidazole-2-butanol (BI2B), an inhibitor of LPS/TLR4-activated transcriptional activity of NF-κB. Methods: Ultraviolet B (UV-B)-irradiated skins of HRM-2 hairless mice and α-MSH-activated melanocyte cultures were employed to examine melanogenic programs. Results: Topical treatment with BI2B ameliorated UV-B-irradiated skin hyperpigmentation in mice. BI2B suppressed the protein or mRNA levels of melanogenic markers, such as tyrosinase (TYR), MITF-M and proopiomelanocortin (POMC), in UV-B-exposed and pigmented skin tissues. Moreover, BI2B inhibited melanin pigmentation in UV-B-irradiated co-cultures of keratinocyte and melanocyte cells and that in α-MSH-activated melanocyte cultures. Mechanistically, BI2B inhibited the activation of cAMP response element-binding protein (CREB) in α-MSH-induced melanogenic programs and suppressed the expression of MITF-M at the promoter level. As a molecular target, BI2B primarily inhibited mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)-catalyzed kinase activity on p38MAPK. Subsequently, BI2B interrupted downstream pathway of p38MAPK-mitogen and stress-activated protein kinase-1 (MSK1)-CREB-MITF-M, and suppressed MITF-M-target melanogenic genes, encoding enzymes TYR, TYR-related protein-1 (TRP-1) and dopachrome tautomerase (DCT) in melanin biosynthesis, and encoding proteins PMEL17 and Rab27A in the transfer of pigmented melanosomes to the overlaying keratinocytes in the skin. Conclusion: Targeting the MKK3-p38MAPK-MSK1-CREB-MITF-M pathway was suggested as a rationale to inhibit UV-B- or α-MSH-induced facultative melanogenesis and as a strategy to prevent acquired pigmentary disorders in the skin.

Project description:Background: The cAMP response element-binding protein (CREB) and CREB-regulated transcription coactivators (CRTCs) cooperate in the transcriptional activation of microphthalmia-associated transcription factor subtype M (MITF-M) that is a master regulator in the biogenesis, pigmentation and transfer of melanosomes at epidermal melanocytes. Here, we propose the targeting of phosphorylation circuits on CREB and CRTCs in the expression of MITF-M as the rationale to prevent skin hyperpigmentation by elucidating the inhibitory activity and mechanism of yakuchinone A (Yaku A) on facultative melanogenesis. Methods: We employed human epidermal melanocyte cell, mouse skin, and mouse melanoma cell, and applied Western blotting, reverse transcription-polymerase chain reaction, immunoprecipitation and confocal microscopy to conduct this study. Results: This study suggested that α-melanocyte stimulating hormone (α-MSH)-induced melanogenic programs could switch on the axis of protein kinase A-salt inducible kinases (PKA-SIKs) rather than that of PKA-AMP activated protein kinase (PKA-AMPK) during the dephosphorylation of CRTCs in the expression of MITF-M. SIK inhibitors rather than AMPK inhibitors stimulated melanin production in melanocyte cultures in the absence of extracellular melanogenic stimuli, wherein SIK inhibitors increased the dephosphorylation of CRTCs but bypassed the phosphorylation of CREB for the expression of MITF-M. Treatment with Yaku A prevented ultraviolet B (UV-B)-irradiated skin hyperpigmentation in mice and inhibited melanin production in α-MSH- or SIK inhibitor-activated melanocyte cultures. Mechanistically, Yaku A suppressed the expression of MITF-M via dually targeting the i) cAMP-dependent dissociation of PKA holoenzyme at the upstream from PKA-catalyzed phosphorylation of CREB coupled with PKA-SIKs axis-mediated dephosphorylation of CRTCs in α-MSH-induced melanogenic programs, and ii) nuclear import of CRTCs after SIK inhibitor-induced dephosphorylation of CRTCs. Conclusions: Taken together, the targeting phosphorylation circuits on CREB and CRTCs in the expression of MITF-M could be a suitable strategy to prevent pigmentary disorders in the skin.

Dataset Information

Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation.

Publications

Stem Cell Factor-Inducible MITF-M Expression in Therapeutics for Acquired Skin Hyperpigmentation.

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