Molecular and Cellular Biochemistry

, Volume 375, Issue 1–2, pp 81–87 | Cite as

Ceramide PC102 inhibits melanin synthesis via proteasomal degradation of microphthalmia-associated transcription factor and tyrosinase

  • Hyo-Soon Jeong
  • Hye-Ryung Choi
  • Hye-Young Yun
  • Kwang Jin Baek
  • Nyoun Soo Kwon
  • Kyoung-Chan Park
  • Dong-Seok Kim
Article

Abstract

A few types of ceramide are reported to decrease melanin synthesis. In the present study, we examined the effects of an artificial ceramide analog, PC102, on melanogenesis using a spontaneously immortalized melanocyte cell line (Mel-Ab). PC102 is currently used as a moisturizing additive in a variety of cosmetics. Our data showed that PC102 inhibited melanin production and tyrosinase activity in a dose-dependent manner, but did not directly affect tyrosinase activity. Microphthalmia-associated transcription factor (MITF), tyrosinase, and β-catenin protein levels decreased after 48 h of PC102 treatment. In contrast, PC102 did not decrease MITF, tyrosinase, and β-catenin mRNA levels. Therefore, we investigated whether the decrease in MITF and tyrosinase by PC102 is due to proteasomal degradation. MG132, a proteasomal inhibitor, completely abolished tyrosinase downregulation due to PC102 and partially reduced the downregulation of MITF and β-catenin due to PC102. Moreover, MG132 abrogated the inhibition of melanin synthesis by PC102. Taken together, our data suggest that PC102 may inhibit melanin synthesis through MITF and tyrosinase degradation.

Keywords

Melanin MITF Tyrosinase Ceramide PC102 

Abbreviations

CT

Cholera toxin

ERK

Extracellular signal-regulated kinase

FBS

Fetal bovine serum

MAPKs

Mitogen-activated protein kinases

GSK3β

Glycogen synthase kinase 3β

MITF

Microphthalmia-associated transcription factor

PC102

1,3-bis(N-2-(hydroxyethyl) lauroylamino)-2-hydroxy propane

TPA

12-O-Tetradecanoylphorbol-13-acetate

TRP

Tyrosinase-related protein

Notes

Acknowledgments

This study was supported by a grant (A100179) from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea.

References

  1. 1.
    Costin GE, Hearing VJ (2007) Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J 21:976–994PubMedCrossRefGoogle Scholar
  2. 2.
    Ando H, Kondoh H, Ichihashi M, Hearing VJ (2007) Approaches to identify inhibitors of melanin biosynthesis via the quality control of tyrosinase. J Invest Dermatol 127:751–761PubMedCrossRefGoogle Scholar
  3. 3.
    Schallreuter KU, Hasse S, Rokos H, Chavan B, Shalbaf M, Spencer JD, Wood JM (2009) Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells. Exp Dermatol 18:680–688PubMedCrossRefGoogle Scholar
  4. 4.
    Kondo T, Hearing VJ (2011) Update on the regulation of mammalian melanocyte function and skin pigmentation. Expert Rev Dermatol 6:97–108PubMedCrossRefGoogle Scholar
  5. 5.
    Levy C, Khaled M, Fisher DE (2006) MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 12:406–414PubMedCrossRefGoogle Scholar
  6. 6.
    Villareal MO, Han J, Yamada P, Shigemori H, Isoda H (2010) Hirseins inhibit melanogenesis by regulating the gene expressions of Mitf and melanogenesis enzymes. Exp Dermatol 19:450–457PubMedCrossRefGoogle Scholar
  7. 7.
    Larue L, Delmas V (2006) The WNT/beta-catenin pathway in melanoma. Front Biosci 11:733–742PubMedCrossRefGoogle Scholar
  8. 8.
    Wu J, Saint-Jeannet JP, Klein PS (2003) Wnt-frizzled signaling in neural crest formation. Trends Neurosci 26:40–45PubMedCrossRefGoogle Scholar
  9. 9.
    Widlund HR, Horstmann MA, Price ER, Cui J, Lessnick SL, Wu M, He X, Fisher DE (2002) Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor. J Cell Biol 158:1079–1087PubMedCrossRefGoogle Scholar
  10. 10.
    Bellei B, Flori E, Izzo E, Maresca V, Picardo M (2008) GSK3beta inhibition promotes melanogenesis in mouse B16 melanoma cells and normal human melanocytes. Cell Signal 20:1750–1761PubMedCrossRefGoogle Scholar
  11. 11.
    Di Nardo A, Benassi L, Magnoni C, Cossarizza A, Seidenari S, Giannetti A (2000) Ceramide 2 (N-acetyl sphingosine) is associated with reduction in Bcl-2 protein levels by Western blotting and with apoptosis in cultured human keratinocytes. Br J Dermatol 143:491–497PubMedCrossRefGoogle Scholar
  12. 12.
    Kim DS, Kim SY, Moon SJ, Chung JH, Kim KH, Cho KH, Park KC (2001) Ceramide inhibits cell proliferation through Akt/PKB inactivation and decreases melanin synthesis in Mel-Ab cells. Pigment Cell Res 14:110–115PubMedCrossRefGoogle Scholar
  13. 13.
    Kim DS, Kim SY, Chung JH, Kim KH, Eun HC, Park KC (2002) Delayed ERK activation by ceramide reduces melanin synthesis in human melanocytes. Cell Signal 14:779–785PubMedCrossRefGoogle Scholar
  14. 14.
    Han WS, Yoo JY, Youn SW, Kim DS, Park KC, Kim SY, Kim KH (2002) Effects of C2-ceramide on the Malme-3M melanoma cell line. J Dermatol Sci 30:10–19PubMedCrossRefGoogle Scholar
  15. 15.
    Dooley TP, Gadwood RC, Kilgore K, Thomasco LM (1994) Development of an in vitro primary screen for skin depigmentation and antimelanoma agents. Skin Pharmacol 7:188–200PubMedCrossRefGoogle Scholar
  16. 16.
    Lee JE, Kim SY, Jeong YM, Yun HY, Baek KJ, Kwon NS, Park KC, Kim DS (2011) The regulatory mechanism of melanogenesis by FTY720, a sphingolipid analogue. Exp Dermatol 20:237–241PubMedCrossRefGoogle Scholar
  17. 17.
    Tsuboi T, Kondoh H, Hiratsuka J, Mishima Y (1998) Enhanced melanogenesis induced by tyrosinase gene-transfer increases boron-uptake and killing effect of boron neutron capture therapy for amelanotic melanoma. Pigment Cell Res 11:275–282PubMedCrossRefGoogle Scholar
  18. 18.
    Busca R, Bertolotto C, Ortonne JP, Ballotti R (1996) Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J Biol Chem 271:31824–31830PubMedCrossRefGoogle Scholar
  19. 19.
    Kim DS, Hwang ES, Lee JE, Kim SY, Kwon SB, Park KC (2003) Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation. J Cell Sci 116:1699–1706PubMedCrossRefGoogle Scholar
  20. 20.
    Khaled M, Larribere L, Bille K, Aberdam E, Ortonne JP, Ballotti R, Bertolotto C (2002) Glycogen synthase kinase 3beta is activated by cAMP and plays an active role in the regulation of melanogenesis. J Biol Chem 277:33690–33697PubMedCrossRefGoogle Scholar
  21. 21.
    Kim DS, Park SH, Kwon SB, Park ES, Huh CH, Youn SW, Park KC (2006) Sphingosylphosphorylcholine-induced ERK activation inhibits melanin synthesis in human melanocytes. Pigment Cell Res 19:146–153PubMedCrossRefGoogle Scholar
  22. 22.
    Takeda K, Takemoto C, Kobayashi I, Watanabe A, Nobukuni Y, Fisher DE, Tachibana M (2000) Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Hum Mol Genet 9:125–132PubMedCrossRefGoogle Scholar
  23. 23.
    Briganti S, Camera E, Picardo M (2003) Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Res 16:101–110PubMedCrossRefGoogle Scholar
  24. 24.
    Solano F, Briganti S, Picardo M, Ghanem G (2006) Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res 19:550–571PubMedCrossRefGoogle Scholar
  25. 25.
    Glickman MH (2000) Getting in and out of the proteasome. Semin Cell Dev Biol 11:149–158PubMedCrossRefGoogle Scholar
  26. 26.
    Nakamura K, Yoshida M, Uchiwa H, Kawa Y, Mizoguchi M (2003) Down-regulation of melanin synthesis by a biphenyl derivative and its mechanism. Pigment Cell Res 16:494–500PubMedCrossRefGoogle Scholar
  27. 27.
    Fujita H, Motokawa T, Katagiri T, Yokota S, Yamamoto A, Himeno M, Tanaka Y (2009) Inulavosin, a melanogenesis inhibitor, leads to mistargeting of tyrosinase to lysosomes and accelerates its degradation. J Invest Dermatol 129:1489–1499PubMedCrossRefGoogle Scholar
  28. 28.
    Park SH, Kim DS, Lee HK, Kwon SB, Lee S, Ryoo IJ, Kim WG, Yoo ID, Park KC (2009) Long-term suppression of tyrosinase by terrein via tyrosinase degradation and its decreased expression. Exp Dermatol 18:562–566PubMedCrossRefGoogle Scholar
  29. 29.
    Busca R, Ballotti R (2000) Cyclic AMP a key messenger in the regulation of skin pigmentation. Pigment Cell Res 13:60–69PubMedCrossRefGoogle Scholar
  30. 30.
    Tachibana M (2000) MITF: a stream flowing for pigment cells. Pigment Cell Res 13:230–240PubMedCrossRefGoogle Scholar
  31. 31.
    Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE (1998) MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 391:298–301PubMedCrossRefGoogle Scholar
  32. 32.
    Wu M, Hemesath TJ, Takemoto CM, Horstmann MA, Wells AG, Price ER, Fisher DZ, Fisher DE (2000) c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 14:301–312PubMedGoogle Scholar
  33. 33.
    Xu W, Gong L, Haddad MM, Bischof O, Campisi J, Yeh ET, Medrano EE (2000) Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9. Exp Cell Res 255:135–143PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Hyo-Soon Jeong
    • 1
  • Hye-Ryung Choi
    • 2
    • 3
  • Hye-Young Yun
    • 1
  • Kwang Jin Baek
    • 1
  • Nyoun Soo Kwon
    • 1
  • Kyoung-Chan Park
    • 2
    • 3
  • Dong-Seok Kim
    • 1
  1. 1.Department of BiochemistryChung-Ang University College of MedicineSeoulRepublic of Korea
  2. 2.Department of DermatologySeoul National University College of MedicineSeoulRepublic of Korea
  3. 3.Department of DermatologySeoul National University Bundang HospitalSeongnam-siRepublic of Korea

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