title: UCHL1 Regulates Melanogenesis through Controlling MITF Stability in Human Melanocytes.
abstract: Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is involved in many signaling pathways via the ubiquitin-proteasome system. UCHL1 is expressed in the human skin and serves as a neuronal marker; however, its functions in melanogenesis remain unknown. Here, we investigated the role of UCHL1 in melanogenesis and elucidated the underlying mechanism using human melanocytes. UCHL1 downregulation by small interfering RNA resulted in upregulation of microphthalmia-associated transcription factor (MITF), tyrosinase, dopachrome tautomerase, tyrosinase-related protein-1, and melanin. In contrast, overexpression of UCHL1 in melanocytes via adenovirus transfection led to downregulation of tyrosinase, dopachrome tautomerase, and tyrosinase-related protein-1 and decreased melanin contents. Furthermore, UCHL1 reduced the protein, but not mRNA, levels of MITF, the upstream regulator of tyrosinase, dopachrome tautomerase, and tyrosinase-related protein-1. Inhibition of de novo protein synthesis and treatment of normal human primary epidermal melanocytes with proteasome inhibitor MG132 revealed that UCHL1 negatively regulates the stability of MITF by binding to the ubiquitinated protein. Finally, overexpression of MITF via an adenovirus restored the level of melanogenesis reduced by UCHL1. Collectively, our findings indicate a role of UCHL1 in regulating skin pigmentation. Suppression of MITF activity by UCHL1 via protein degradation might aid in the development of new therapeutic approaches for melanoma or dyspigmentation disorders.
authors.affiliation: Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environmental Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Seo
authors.affiliation: Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environmental Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea; Deparment of Biomedical Science, Seoul National University Graduate School, Seoul, Republic of Korea.
authors.forename: Seon-Pil
authors.initials: SP
authors.lastname: Jin
authors.affiliation: Department of Dermatology and Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Kyung-Cheol
authors.initials: KC
authors.lastname: Sohn
authors.affiliation: Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environmental Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Chi-Hyun
authors.initials: CH
authors.lastname: Park
authors.affiliation: Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environmental Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea. Electronic address: ivymed27@snu.ac.kr.
authors.forename: Dong Hun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environmental Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea; Deparment of Biomedical Science, Seoul National University Graduate School, Seoul, Republic of Korea. Electronic address: jhchung@snu.ac.kr.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Chung
mesh_terms: D015153:Blotting, Western; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis / Q000235:genetics*; D000096142:Cutaneous Malignant Melanoma
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D012334:RNA, Neoplasm; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase