title: Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes.
abstract: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan; Inter Departmental Multidisciplinary Graduate Program in Bioscience, Faculty of Science, Kasetsart University, Bangkok, Thailand.
authors.forename: Wipa
authors.initials: W
authors.lastname: Chantarawong
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Weerapon
authors.initials: W
authors.lastname: Sangartit
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Yoshizawa
authors.affiliation: Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, Thailand.
authors.forename: Kantimanee
authors.initials: K
authors.lastname: Pradermwong
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan. Electronic address: shibahar@med.tohoku.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibahara
mesh_terms: D000328:Adult; D002104:Cadmium / Q000008:administration & dosage / Q000633:toxicity*; D002460:Cell Line; D005260:Female; D006801:Humans; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D002104:Cadmium
keywords: Cadmium; Melanocyte; Melanoma; Microphthalmia-associated transcription factor; Retinal pigment epithelium; Tyrosinase