title: The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc.
abstract: c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCF(Fbw7) (a SKP1-cullin-1-F-box complex that contains the F-box and WD repeat domain-containing 7, Fbw7, as the F-box protein) and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) 28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ but not the nucleoplasmic Fbw7α. However, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc's nucleolar degradation pathway.
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239;
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Sun
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing 210000, China; and.
authors.forename: Xia
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing 210000, China; and.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239; daim@ohsu.edu searsr@ohsu.edu.
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239; daim@ohsu.edu searsr@ohsu.edu.
authors.forename: Mu-Shui
authors.initials: MS
authors.lastname: Dai
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016271:Proto-Oncogene Proteins c-myc; C501066:USP36 protein, human; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; D043222:Ubiquitin Thiolesterase
keywords: USP36; c-Myc; deubiquitination; nucleolus; ubiquitination