title: Geranylgeranylacetone inhibits melanin synthesis via ERK activation in Mel-Ab cells.
abstract: OBJECTIVE
  Geranylgeranylacetone (GGA) has shown cytoprotective activity through induction of a 70-kDa heat shock protein (HSP70). Although HSP70 is reported to regulate melanogenesis, the effects of GGA on melanin synthesis in melanocytes have not been previously studied. Therefore, this study investigated the effects of GGA on melanogenesis and the related signaling pathways.
  
  
  METHODS
  Melanin content and tyrosinase activities were measured in Mel-Ab cells. GGA-induced signal transduction pathways were investigated by western blot analysis.
  
  
  RESULTS
  Our results showed that GGA significantly decreased melanin content in a concentration-dependent manner. Similarly, GGA reduced tyrosinase activity dose-dependently, but it did not directly inhibit tyrosinase. Western blot analysis indicated that GGA downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase protein expression, whereas it increased the phosphorylation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Furthermore, a specific ERK pathway inhibitor, PD98059, blocked GGA-induced melanin reduction and then prevented downregulation of MITF and tyrosinase by GGA. However, a specific mTOR inhibitor, rapamycin, only slightly restored inhibition of melanin production by GGA, indicating that mTOR signaling is not a key mechanism regulating the inhibition of melanin production.
  
  
  CONCLUSIONS
  These findings suggest that activation of ERK by GGA reduces melanin synthesis in Mel-Ab cells through downregulation of MITF and tyrosinase expression.
authors.affiliation: Department of Biochemistry, Chung-Ang University College of Medicine, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Eun-Hyun
authors.initials: EH
authors.lastname: Kim
authors.forename: Hyo-Soon
authors.initials: HS
authors.lastname: Jeong
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Yun
authors.forename: Kwang Jin
authors.initials: KJ
authors.lastname: Baek
authors.forename: Nyoun Soo
authors.initials: NS
authors.lastname: Kwon
authors.forename: Kyoung-Chan
authors.initials: KC
authors.lastname: Park
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology*; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D008543:Melanins; D048049:Extracellular Signal-Regulated MAP Kinases; C031049:geranylgeranylacetone
keywords: ERK; Geranylgeranylacetone; MITF; Melanogenesis; Tyrosinase