title: Aberrant activation, nuclear localization, and phosphorylation of Yes-associated protein-1 in the embryonic kidney and Wilms tumor.
abstract: BACKGROUND
  The Yes-associated-protein-1 (YAP1) is a novel, direct regulator of stem cell genes both in development and cancer. FAT4 is an upstream regulator that induces YAP1 cytosolic sequestering by phosphorylation (p-Ser 127) and therefore inhibits YAP1-dependent cellular proliferation. We hypothesized that loss of FAT4 signaling would result in expansion of the nephron progenitor population in kidney development and that YAP1 subcellular localization would be dysregulated in Wilms tumor (WT), an embryonal malignancy that retains gene expression profiles and histologic features reminiscent of the embryonic kidney.
  
  
  METHODS
  Fetal kidneys from Fat4(-/-) mice were harvested at e18.5 and markers of nephron progenitors were investigated using immunohistochemical analysis. To examine YAP1 subcellular localization in WT, a primary WT cell line (VUWT30) was analyzed by immunofluorescence. Forty WT specimens evenly distributed between favorable and unfavorable histology (n = 20 each), and treatment failure or success (n = 20 each) was analyzed for total and phosphorylated YAP1 using immunohistochemistry and Western blot.
  
  
  RESULTS
  Fat4(-/-) mouse fetal kidneys exhibit nuclear YAP1 with increased proliferation and expansion of nephron progenitor cells. In contrast to kidney development, subcellular localization of YAP1 is dysregulated in WT, with a preponderance of nuclear p-YAP1. By Western blot, median p-YAP1 quantity was 5.2-fold greater in unfavorable histology WT (P = 0.05).
  
  
  CONCLUSIONS
  Fetal kidneys in Fat4(-/-) mice exhibit a phenotype reminiscent of nephrogenic rests, a WT precursor lesion. In WT, YAP1 subcellular localization is dysregulated and p-YAP1 accumulation is a novel biomarker of unfavorable histology.
authors.affiliation: Department of Pediatric Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Janene
authors.initials: J
authors.lastname: Pierce
authors.forename: Christian
authors.initials: C
authors.lastname: de Caestecker
authors.forename: Jaime
authors.initials: J
authors.lastname: Libes
authors.forename: David
authors.initials: D
authors.lastname: Neblett
authors.forename: Mark
authors.initials: M
authors.lastname: de Caestecker
authors.forename: Alan O
authors.initials: AO
authors.lastname: Perantoni
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tanigawa
authors.forename: James R
authors.initials: JR
authors.lastname: Anderson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Dome
authors.forename: Amrita
authors.initials: A
authors.lastname: Das
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carroll
authors.forename: Harold N
authors.initials: HN
authors.lastname: Lovvorn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002675:Child, Preschool; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D021381:Protein Transport; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013347:Subcellular Fractions; D014157:Transcription Factors; D009396:Wilms Tumor / Q000378:metabolism / Q000473:pathology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse
keywords: Wilms tumor; YAP1; anaplasia; biomarker; nephrogenic rests