Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Studies of Inhibitory Mechanism on Melanogenesis by Partially Purified Asiasari radix in α-MSH Stimulated B16F10 Melanoma Cells

세신추출물이 α-MSH 자극에 의한 B16F10 세포의 멜라닌생성에 미치는 영향

  • Jang, Ji-Yeon (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Kim, Ha-Neui (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Kim, Yu-Ri (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Kim, Byung-Woo (Department of Life Science and Biotechnology, College of Natural Sciences, Dongeui University) ;
  • Choi, Yung-Hyun (Department of Biochemistry, College of Oriental Medicine, Dongeui University) ;
  • Choi, Byung-Tae (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University)
  • 장지연 (부산대학교 한의학전문대학원 경락구조의학부) ;
  • 김하늬 (부산대학교 한의학전문대학원 경락구조의학부) ;
  • 김유리 (부산대학교 한의학전문대학원 경락구조의학부) ;
  • 김병우 (동의대학교 자연과학대학 생명응용과학과) ;
  • 최영현 (동의대학교 한의과대학 생화학교실) ;
  • 최병태 (부산대학교 한의학전문대학원 경락구조의학부)
  • Received : 2010.07.20
  • Accepted : 2010.11.03
  • Published : 2010.11.30
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Abstract

Recently, it has been found that Asiasari radix showed a hypopigmenting effect on melanogenesis through activation of mitogen-activated protein kinase (MEK)/extracellular signal-activated kinase (ERK) in B16F10 melanoma cells. However, the hypopigmenting effect of A. radix on the $\alpha$-melanocyte stimulating hormone ($\alpha$-MSH)-stimulated melanogenesis has remained unknown. The purpose of this study was to investigate the inhibitory mechanism of the partially purified A. radix (PPAR)-induced hypopigmentating effects on $\alpha$-MSH-stimulated melanogenesis in B16F10 mouse melanoma cells. PPAR strongly inhibited tyrosinase activity and leads to decreased melanin synthesis in $\alpha$-MSH-stimulated B16F10 melanoma cells. PPAR also decreased the $\alpha$-MSH-induced over-expression of the melanogenic enzymes, tyrosinase, tyrosinase-related protein (TRP)-1, dopachrome tautomerase (Dct) and microphthalmia-associated transcription factor (MITF). We further showed that PPAR inhibits $\alpha$-MSH-induced melanogenesis via phosphorylation of MEK/ERK and PI3K/Akt, and that their activation was blocked by MEK inhibitors, PD98059 and PI3K inhibitors, LY294002 in $\alpha$-MSH-stimulated B16F10 melanoma cells. These results suggest that PPAR inhibits $\alpha$-MSH-induced melanogenesis by activation of MEK/ERK and PI3K/Akt through MITF degradation, which may lead to down-regulation of tyrosinase.

$\alpha$-MSH는 세포내 cAMP를 증폭시켜 멜라닌세포의 증식과 색소 증가에 관여한다. 본 연구에서는 $\alpha$-MSH로 자극한 B16F10 세포에서 세신추출물의 hypopigmenting 효과를 조사하고 그 억제기전에 대하여 조사하였다. 세신추출물은 $\alpha$-MSH에 의해 유도된 tyrosinase 활성과 멜라닌생성을 효과적으로 억제시켰으며, 이는 tyrosinase 발현을 조절하는 전사인자인 MITF의 발현억제와 연관성이 있었다. 즉 세신추출물은 MEK/ERK와 PI3K/Akt의 활성화를 통하여 MITF를 조절함으로서 $\alpha$-MSH에 의해 유도되는 tyrosinase, TRP-1, Dct 등 멜라닌생성관련 단백질을 억제함으로서 멜라닌생성을 저해하는 것으로 사료된다.

Keywords

References

  1. Bertolotto, C., P. Abbe, T. J. Hemesath, K. Bille, D. E. Fisher, J. P. Ortonne, and R. Ballotti. 1998. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J. Cell Biol. 142, 827-835. https://doi.org/10.1083/jcb.142.3.827
  2. Bertolotto, C., R. Busca, P. Abbe, K. Bille, E. Aberdam, J. P. Ortonne, and R. Ballotti. 1998. Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. Mol. Cell Biol. 18, 694-702.
  3. Chakraborty, A. K., Y. Funasaka, A. Slominski, G. Ermak, J. Hwang, J. M. Pawelek, and M. Ichihashi. 1996. Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B. Biochim. Biophys. Acta. 1313, 130-138. https://doi.org/10.1016/0167-4889(96)00063-8
  4. Cheli, Y., F. Luciani, M. Khaled, L. Beuret, K. Bille, P. Gounon, J. P. Ortonne, C. Bertolotto, and R. Ballotti. 2009. Alpha-MSH and Cyclic AMP elevating agents control melanosome pH through a protein kinase A-independent mechanism. J. Biol. Chem. 284, 18699-18706. https://doi.org/10.1074/jbc.M109.005819
  5. Coffer, P. J., J. Jin, and R. Woodgett. 1998. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem. J. 335, 1-13.
  6. Costin, G. E. and V. J. Hearing. 2007. Human skin pigmentation: melanocytes modulate skin color in response to stress. FASEB J. 21, 976-994. https://doi.org/10.1096/fj.06-6649rev
  7. Fuller, B. B., J. B. Lunsford, and D. S. Iman. 1987. Alpha-melanocyte-stimulating hormone regulation of tyrosinase in Cloudman S-91 mouse melanoma cell cultures. J. Biol. Chem. 262, 4024-4033.
  8. Funasaka, Y. A., K. Chakraborty, Y. Hayashi, M. Komoto, A. Ohashi, M. Nagahama, Y. Inoue, J. Pawelek, and M. Ichihashi. 1998. Modulation of melanocyte-stimulating hormone receptor expression on normal human melanocytes: evidence for a regulatory role of ultraviolet B, interleukin-1${\alpha}$, interleukin-1${\beta}$, endothelin-1 and tumour necrosis factor-${\alpha}$. Br. J. Dermatol. 139, 216-224. https://doi.org/10.1046/j.1365-2133.1998.02357.x
  9. Han, Y. and S. J. Kim. 2003. Memory enhancing actions of Asiasari radix extracts via activation of insulin receptor and extracellular signal regulated kinase (ERK) I/II in rat hippocampus. Brain Res. 974, 193-201. https://doi.org/10.1016/S0006-8993(03)02580-0
  10. Hemesath, T. J., E. R. Price, C. Takemoto, T. Bagdalian, and D. E. Fisher. 1998. MAP kinase links the transcription factor Microphthalmia to c-kit signaling in melanoytes. Nature 391, 298-301. https://doi.org/10.1038/34681
  11. Hemmings, B. A. 1997. Akt signaling: linking membrane events to life and death decisions. Science 275, 628-630. https://doi.org/10.1126/science.275.5300.628
  12. Hunt, G., C. Todd, J. E. Cresswell, and A. J. Thody. 1994. Alpha-melanocyte stimulating hormone and its analogue $Nle^{4}DPhe^{7}alpha$-MSH affect morphology, tyrosinase activity and melanogenesis in cultured human melanocytes. J. Cell Sci. 107, 205-211.
  13. Jang, J. Y., J. H. Lee, H. K. Shin, Y. H. Choi, J. D. Lee, and B. T. Choi. 2010. Partially purified Asiasari radix inhibits melanogenesis through extracellular signal-regulated kinase signaling in B16F10 cells. Int. J. Mol. Med. 25, 287-292.
  14. Kim, D. S., E. S. Hwang, J. E. Lee, S. Y. Kim, S. B. Kwon, and K. C. Park. 2003. Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation. J. Cell Sci. 116, 1699-1706. https://doi.org/10.1242/jcs.00366
  15. Kim, D. S., S. Y. Kim, J. H. Chung, K. H. Kim, H. C. Eun, and K. C. Park. 2002. Delayed ERK activation by ceramide reduces melanin synthesis in human melanocytes. Cell Signal 14, 779-785. https://doi.org/10.1016/S0898-6568(02)00024-4
  16. Kim, D. S., S. Y. Kim, S. J. Moon, J. H. Chung, K. H. Kim, K. H. Cho, and K. C. Park. 2001. Ceramide inhibits cell proliferation through Akt/PKB inactivation and decreases melanin synthesis in Mel-Ab cells. Pigment Cell Res. 14, 110-115. https://doi.org/10.1034/j.1600-0749.2001.140206.x
  17. Kumar, K., J. C. Yang, F. H. Chu, S. T. Chang, and S. Y. Wang. 2010. Lucidone, a novel melanin inhibitor from the fruit of Lindera erythrocarpa Makino. Phytother. Res. 24, 1156-1165.
  18. Lee, J. Y., S. S. Moon, and B. K. Hwang. 2005. Isolation and antifungal activity of kakuol, a propiophenone derivative from Asarum sieboldii rhizome. Pest. Manag. Sci. 61, 821-825. https://doi.org/10.1002/ps.1050
  19. Lee, J., E. Jung, J. Lee, S. Huh, Y. C. Boo, C. G. Hyun, Y. S. Kim, and D. Park. 2007. Mechanisms of melanogenesis inhibition by 2,5-dimethyl-4-hydroxy-3(2H)-furanone. Br. J. Dermatol. 157, 242-248. https://doi.org/10.1111/j.1365-2133.2007.07934.x
  20. Lee, J., K. Jung, Y. S. Kim, and D. Park. 2007. Diosgenin inhibits melanogenesis through the activation of phosphatidylinositol-3-kinase pathway (PI3K) signaling. Life Sci. 81, 249-254. https://doi.org/10.1016/j.lfs.2007.05.009
  21. Park, H. Y., C. Wu, L. Yonemoto, M. Murphy-Smith, H. Wu, C. M. Stachur, and B. A. Gilchrest. 2006. MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes. Biochem. J. 395, 571-578. https://doi.org/10.1042/BJ20051388
  22. Price, E. R., H. F. Ding, T. Badalian, S. Bhattacharya, C. Takemoto, T. P. Yao, T. J. Hemesath, and D. E. Fisher. 1998. Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia. J. Biol. Chem. 273, 17983-17986. https://doi.org/10.1074/jbc.273.29.17983
  23. Schwahn, D. J., W. Xu, A. B. Herrin, E. S. Bales, and E. E. Medrano. 2001. Tyrosine levels regulate the melanogenic response to alpha-melanocyte-stimulating hormone in human melanocytes: implications for pigmentation and proliferation. Pigment Cell Res. 14, 32-39. https://doi.org/10.1034/j.1600-0749.2001.140106.x
  24. Suzuki, Y., M. Yuzurihara, T. Hibino, S. Yano, and Y. Kase. 2009. Aqueous extract of Asiasari radix inhibits formalin-induced hyperalgesia NMDA receptors. J. Ethnopharmacol. 123, 128-133. https://doi.org/10.1016/j.jep.2009.02.005
  25. Xu, W., L. Gong, M. M. Haddad, O. Bischof, J. Campisi, E. T. Yeh, and E. E. Medrano. 2000. Regulation of Microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugation enzyme hUBC9. Exp. Cell Res. 255, 135-143. https://doi.org/10.1006/excr.2000.4803
  26. Yokoyama, K., H. Suzki, K. Yasumoto, Y. Tomita, and S. Shibahara. 1994. Molecular cloning and functional analysis of a cDNA coding for human DOPAchrome tautomerase/tyrosinase-related protein-2. Biochem. Biophys. Acta. 1217, 317-321. https://doi.org/10.1016/0167-4781(94)90292-5

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