Regulation of MITF stability by the USP13 deubiquitinase

Xiansi Zhao, Brian Fiske, Akinori Kawakami, Juying Li and David E Fisher ()
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Xiansi Zhao: Cutaneous Biology Research Center & Melanoma Program, Massachusetts General Hospital, Harvard Medical School
Brian Fiske: Cutaneous Biology Research Center & Melanoma Program, Massachusetts General Hospital, Harvard Medical School
Akinori Kawakami: Cutaneous Biology Research Center & Melanoma Program, Massachusetts General Hospital, Harvard Medical School
Juying Li: Cutaneous Biology Research Center & Melanoma Program, Massachusetts General Hospital, Harvard Medical School
David E Fisher: Cutaneous Biology Research Center & Melanoma Program, Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2011, vol. 2, issue 1, 1-8

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1421

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