title: Ubiquitin specific protease 18 (Usp18) is a WT1 transcriptional target.
abstract: Wilms tumor gene WT1 encodes a zinc finger-containing transcription factor which is required for renal development. Mutations in WT1 are observed in 20% of Wilms tumors (a pediatric kidney cancer), but the in vivo WT1 targets and associated molecular pathways involved in the etiology of Wilms tumor are still elusive. To identify WT1 targets we performed genome-wide comprehensive expression profiling using Affymetrix Gene Chip Mouse Genome 430 2.0 Arrays, comparing E13.5 mouse kidneys in which Wt1 had been somatically ablated with littermate controls. We identified Usp18 as the most differentially expressed gene in mutant kidney. Using tetracycline inducible cells we demonstrated a repressive effect of WT1 on USP18 expression. Conversely, knockdown of WT1 led to the upregulation of Usp18. Furthermore, direct binding of WT1 to the Usp18 promoter was demonstrated by ChIP assay. Overexpression of USP18 in murine and human cell lines resulted in cell proliferation. Additionally, Usp18 upregulation was observed in a mouse model of Wilms tumor. Taken together our data demonstrate that Usp18 is a transcriptional target of WT1 and suggest that increased expression of USP18 following WT1 loss contributes to Wilms tumorigenesis.
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1010, Houston, TX 77030, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahidul Makki
authors.forename: E
authors.initials: E
authors.lastname: Cristy Ruteshouser
authors.forename: Vicki
authors.initials: V
authors.lastname: Huff
mesh_terms: D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015533:Transcriptional Activation; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D025721:WT1 Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009396:Wilms Tumor / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D025721:WT1 Proteins; D008156:Luciferases; D010450:Endopeptidases; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase