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Withaferin A abolishes the stem cell factor-stimulated pigmentation of human epidermal equivalents by interrupting the auto-phosphorylation of c-KIT in human melanocytes

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Abstract

We characterized the mechanism(s) underlying the abrogating effect of withaferin A (WFA) on the stem cell factor (SCF)-stimulated pigmentation of human epidermal equivalents (HEEs). Increased gene and protein expression levels of tyrosinase, tyrosinase-related protein1, dopachrome tautomerase, PMEL17, c-KIT and their targeted transcription factor, microphthalmia-associated transcription factor (MITF) were significantly reversed at days 7 and 10, respectively, by treatment with WFA. In WFA-treated normal human melanocytes (NHMs), there was a marked deficiency in the SCF-stimulated series of phosphorylations of c-KIT, Shc, Raf-1, MEK, ERK, MITF and CREB. Treatment with dithiothreitol (DTT) distinctly abolished the suppressive effect of WFA on the SCF-stimulated phosphorylation of c-KIT in NHMs. On the other hand, even after incubation at 4 °C for 2 h with 5 nM SCF, followed by the removal of unbound SCF by washing and then raising the temperature to 37 °C to start the signaling reaction, c-KIT was distinctly phosphorylated to a similar extent by incubation for 15 min with SCF only or with SCF + WFA. These findings indicate that WFA attenuates the SCF-induced activation of c-KIT in NHMs by interrupting the auto-phosphorylation of c-KIT through DTT-suppressible Michael addition thioalkylation reactions without interrupting the binding of SCF to the c-KIT receptor.

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Abbreviations

WFA:

Withaferin A

SCF:

Stem cell factor

EDN:

Endothelin

MSH:

Melanocyte stimulating hormone

HEE:

Human epidermal equivalent

MAPK:

Mitogen activated protein kinase

MITF:

Microphthalmia-associated transcription factor

NHM:

Normal human melanocyte

TYRP1:

Tyrosinase-related protein1

TYR:

Tyrosinase

DCT:

Dopachrome tautomerase

EDNBR:

Endothelin B receptor

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

PTCA:

Pyrrole-2,3,5-tricarboxylic acid

MBTH:

3-Methyl-2-benzothiazolinone hydrazine

DTT:

Dithiothreitol

BSA:

Bovine serum albumin

FM:

Fontana Masson

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Acknowledgments

We acknowledge Professor K. Wakamatsu for kindly providing PTCA standard. Shuko Terazawa designed the research study, performed the research and wrote the paper. Hiroaki Nakajima and Katsunori Fukasawa performed the research. Genji Imokawa designed the research study and wrote the paper.

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The authors have declared that no conflict of interest exists.

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Authors and Affiliations

  1. Research Institute for Biological Functions, Chubu University, 1200 Matsumoto, Kasugai, Aichi, 487-8501, Japan

    Shuko Terazawa & Genji Imokawa

  2. School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo, 192-0982, Japan

    Hiroaki Nakajima & Katsunori Fukasawa

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  1. Shuko Terazawa
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  2. Hiroaki Nakajima
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Correspondence to Genji Imokawa.

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S. Terazawa and H. Nakajima contributed equally to this work.

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Terazawa, S., Nakajima, H., Fukasawa, K. et al. Withaferin A abolishes the stem cell factor-stimulated pigmentation of human epidermal equivalents by interrupting the auto-phosphorylation of c-KIT in human melanocytes. Arch Dermatol Res 307, 73–88 (2015). https://doi.org/10.1007/s00403-014-1518-y

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