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Sci Rep ; 14(1): 9440, 2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658799

RESUMO

Although previous studies have examined the signaling pathway involved in melanogenesis through which ultraviolet (UV) or α-melanocyte-stimulating hormones (α-MSH) stimuli act as key inducers to produce melanin at the stratum basal layer of the epidermis, the signaling pathway regulating melanogenesis is still controversial. This study reports that α-MSH, not UVA and UVB, acted as a major stimulus of melanogenesis in B16F10 melanoma cells. Signaling pathway analysis using gene knockdown technology and chemical inhibitors, the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 2 (RSK2) played an important role in melanogenesis. Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis. Chemical inhibition of the MEKs/ERKs/RSK2 signaling pathway using U0126 or BI-D1870 suppressed melanogenesis by stimulation of UVA or α-MSH stimulation, or both. In particular, the genetic depletion of RSK2 or constitutive active (CA)-RSK2 overexpression showed that RSK2 plays a key role in melanogenesis. Interestingly, forkhead box protein O4 (FOXO4) was phosphorylated by RSK2, resulting in the increase of FOXO4's transactivation activity. Notably, the FOXO4 mutant harboring serine-to-alanine replacement at the phosphorylation sites totally abrogated the transactivation activity and reduced melanin production, indicating that RSK2-mediated FOXO4 activity plays a key role in melanogenesis. Furthermore, kaempferol, a flavonoid inhibiting the RSK2 activity, suppressed melanogenesis. In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis.


Assuntos
Melaninas , Pteridinas , Proteínas Quinases S6 Ribossômicas 90-kDa , Transdução de Sinais , alfa-MSH , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Melaninas/biossíntese , Melaninas/metabolismo , Animais , alfa-MSH/metabolismo , alfa-MSH/farmacologia , Camundongos , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Raios Ultravioleta , Morfolinas/farmacologia , Cromonas/farmacologia , Nitrilas/farmacologia , Butadienos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Melanoma Experimental/metabolismo , Melanogênese
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