Daphnetin inhibits α-MSH-induced melanogenesis via PKA and ERK signaling pathways in B16F10 melanoma cells

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ABSTRACT

Daphnetin is a dehydroxylated derivative of coumarin isolated from Daphne species. However, the effect of daphnetin on melanogenesis has not been elucidated. This study aims to investigate the inhibitory effect of daphnetin on melanogenesis in α-melanocyte stimulating hormone (α-MSH)-treated B16F10 cells and its potential mechanism. Melanin content analysis and cellular tyrosinase activity assay showed that daphnetin inhibited melanin biosynthesis in α-MSH-treated B16F10 cells. Immunoblotting and qRT-PCR also indicated that daphnetin suppressed the expression of microphthalmia-associated transcription factor, a mastering transcription factor of melanogenesis and its downstream melanogenic enzymes including tyrosinase and tyrosinase-related proteins. Moreover, daphnetin downregulated the phosphorylation of PKA, ERK, MSK1, and CREB. Additionally, daphnetin inhibited melanin synthesis in UVB-irradiated HaCaT conditioned medium system suggesting that daphnetin has potential as an antipigmentation activity in a physiological skin condition. Our data propose that daphnetin inhibits melanogenesis via modulating both the PKA/CREB and the ERK/MSK1/CREB pathways.

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Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.

G. Gonzalez, M Montminy (1989)

In this paper, we demonstrate that phosphorylation of CREB at Ser-133 is induced 6-fold in vivo, following treatment of PC12 cells with forskolin. By contrast, no such induction was observed in the kinase A-deficient PC12 line A126-1B2 (A126). Using F9 teratocarcinoma cells, which are unresponsive to cAMP, we initiated a series of transient expression experiments to establish a causal link between phosphorylation of CREB and trans-activation of cAMP-responsive genes. Inactivating the kinase A phosphorylation site by in vitro mutagenesis of the cloned CREB cDNA at Ser-133 completely abolished CREB transcriptional activity. As CREB mutants containing acidic residues in place of the Ser-133 phosphoacceptor were also transcriptionally inactive, these results suggest that phosphorylation of CREB may stimulate transcription by a mechanism other than by simply providing negative charge.

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Melanin pigmentation in mammalian skin and its hormonal regulation.

Andrzej T. Slominski, Martin D. Tobin, J Wortsman … (2004)

Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and -independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple linear sequences, but they interphase instead in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized. Within the context of the skin as a stress organ, melanogenic activity serves as a unique molecular sensor and transducer of noxious signals and as regulator of local homeostasis. In keeping with these multiple roles, melanogenesis is controlled by a highly structured system, active since early embryogenesis and capable of superselective functional regulation that may reach down to the cellular level represented by single melanocytes. Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait.

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Signaling Pathways in Melanogenesis

Stacey A. N. D’Mello, Graeme Finlay, Bruce C. Baguley … (2016)

Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.

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Author and article information

Contributors

Seunghee Bae: (View ORCID Profile)

Journal

Title: Bioscience, Biotechnology, and Biochemistry

Publisher: Oxford University Press (OUP)

ISSN (Electronic): 1347-6947

Publication date Created: May 2022

Publication date Created: April 21 2022

Publication date Created: March 23 2022

Publication date Other: May 2022

Publication date (Print): April 21 2022

Publication date (Electronic): March 23 2022

Volume: 86

Issue: 5

Pages: 596-609

Affiliations

[1 ]Department of Cosmetics Engineering, Konkuk University, Seoul, Republic of Korea

[2 ]Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gu, Seoul, Republic of Korea

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DOI: 10.1093/bbb/zbac016

PubMed ID: 35325017

SO-VID: 287560fb-d545-4ced-95cb-dd10185fc368

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https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

Daphnetin inhibits α-MSH-induced melanogenesis via PKA and ERK signaling pathways in B16F10 melanoma cells

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Neuronal Signaling

Most cited references 76

Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.

Melanin pigmentation in mammalian skin and its hormonal regulation.

Signaling Pathways in Melanogenesis

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