Inhibition of MITF and tyrosinase by paeonol-stimulated JNK/SAPK to reduction of phosphorylated CREB.
Tyrosinase and its transcriptional regulator microphthalmia-associated transcription factor (MITF) play critical roles in regulation of melanogenesis, and are required for environmental cues or agents in modulation of melanin synthesis. Identifying the signals regulating tyrosinase and MITF is crucial to understanding how pigmentation responds to extracellular stimuli. In this report, we discovered that paeonol down-regulated melanin production via decreasing MITF expression and consequent mRNA and protein levels of tyrosinase. We also found that paeonol reduced phosphorylation of a cAMP responsive element binding protein (phospho-CREB), which binds and activates MITF. A selective inhibitor of c-jun N-terminal or stress-activated protein kinases (JNK/SAPK)-SP600125 significantly reversed paeonol-induced down-regulation of melanogenesis. Inhibition of cAMP/PKA pathway intensified the hypopigmentation response to paeonol. These results identify a mechanism in which paeonol induces the down-regulation of melanogenesis through inhibition of CREB phosphorylation, leading to the expression reduction of MITF and subsequently tyrosinase. The key kinase mediating the effects of paeonol on melanogenesis in B16F10 cells is JNK/SAPK. Additionally, the cAMP/PKA pathway may take part in this process.
Bu
Jin
J
Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, China.
Ma
Peng-Cheng
PC
Chen
Zhi-Qiang
ZQ
Zhou
Wu-Qing
WQ
Fu
You-Jun
YJ
Li
Ling-Jun
LJ
Li
Cheng-Rang
CR
D000098:Acetophenones / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000209:etiology* / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000502:physiology; D014442:Monophenol Monooxygenase / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000098:Acetophenones; D017362:Cyclic AMP Response Element-Binding Protein; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D012333:RNA, Messenger; C013638:paeonol; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases