title: Regulation of MITF stability by the USP13 deubiquitinase.
abstract: The microphthalmia-associated transcription factor (MITF) is essential for melanocyte development. Mutation-induced MAPK pathway activation is common in melanoma and induces MITF phosphorylation, ubiquitination, and proteolysis. Little is known about the enzymes involved in MITF ubiquitination/deubiquitination. Here we report the identification of a deubiquitinating enzyme, named ubiquitin-specific protease 13 (USP13) that appears to be responsible for MITF deubiquitination, utilizing a short hairpin RNA library against known deubiquitinating enzymes. Through deubiquitination, USP13 stabilizes and upregulates MITF protein levels. Conversely, suppression of USP13 (through knockdown) leads to dramatic loss of MITF protein, but not messenger RNA. Through its effects on MITF deubiquitination, USP13 was observed to modulate expression of MITF downstream target genes and, thereby, to be essential for melanoma growth in soft agar and in nude mice. These observations suggest that as a potentially drugable protease, USP13 might be a viable therapeutic target for melanoma.
authors.affiliation: Cutaneous Biology Research Center & Melanoma Program, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
authors.forename: Xiansi
authors.initials: X
authors.lastname: Zhao
authors.forename: Brian
authors.initials: B
authors.lastname: Fiske
authors.forename: Akinori
authors.initials: A
authors.lastname: Kawakami
authors.forename: Juying
authors.initials: J
authors.lastname: Li
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D010450:Endopeptidases; C561638:USP13 protein, human; D064570:Ubiquitin-Specific Proteases