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Ribosomal S6 kinase 2-forkhead box protein O4 signaling pathway plays an essential role in melanogenesis.
- Source :
-
Scientific reports [Sci Rep] 2024 Apr 24; Vol. 14 (1), pp. 9440. Date of Electronic Publication: 2024 Apr 24. - Publication Year :
- 2024
-
Abstract
- 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Cell Line, Tumor
Forkhead Transcription Factors metabolism
Forkhead Transcription Factors genetics
Ultraviolet Rays
Morpholines pharmacology
Chromones pharmacology
Nitriles pharmacology
Butadienes pharmacology
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation
Melanoma, Experimental metabolism
Melanogenesis
Ribosomal Protein S6 Kinases, 90-kDa metabolism
Ribosomal Protein S6 Kinases, 90-kDa genetics
Melanins biosynthesis
Melanins metabolism
alpha-MSH metabolism
alpha-MSH pharmacology
Signal Transduction
Pteridines
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 38658799
- Full Text :
- https://doi.org/10.1038/s41598-024-60165-9