Long-term suppression of tyrosinase by terrein via tyrosinase degradation and its decreased expression.
Previously, we reported that a fungal metabolite, terrein, decreases melanin synthesis via downregulation of microphthalmia-associated transcription factor (MITF). In the present study, we further investigated the long-term hypopigmenting action of terrein in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment with terrein at a concentration of 50 mum strongly decreased melanogenesis in a time-dependent manner. Interestingly, the decreased tyrosinase protein levels lasted for at least 7 days, even though the MITF protein levels were restored after 3 days of treatment. In accordance with the results of Western blot analyses, the tyrosinase mRNA levels were found to be continuously decreased for at least 7 days, even though recovery of the MITF mRNA levels began after 3 days of terrein treatment. Therefore, we evaluated tyrosinase downregulation to determine if it is caused by proteasomal degradation. We found that the reduction in tyrosinase levels that was induced by terrein was clearly recovered by MG-132, a proteasome inhibitor. Moreover, ubiquitination of tyrosinase increased following treatment with terrein in the presence of MG-132. Taken together, these results suggest that terrein decreases melanogenesis through ubiquitin-dependent proteasomal degradation as well as via decreased expression of its mRNA.
Park
Seo-Hyoung
SH
Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.
Kim
Dong-Seok
DS
Lee
Hyun-Kyung
HK
Kwon
Sun-Bang
SB
Lee
Sangku
S
Ryoo
In-Ja
IJ
Kim
Won-Gon
WG
Yoo
Ick-Dong
ID
Park
Kyoung-Chan
KC
D000818:Animals; D002461:Cell Line, Transformed / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D007976:Leupeptins / Q000494:pharmacology; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054875:Ubiquitination / Q000187:drug effects
D003517:Cyclopentanes; D007976:Leupeptins; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C439087:terrein; D014442:Monophenol Monooxygenase; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde