Aberrant activation, nuclear localization, and phosphorylation of Yes-associated protein-1 in the embryonic kidney and Wilms tumor.
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.
['Murphy|Andrew J|AJ|', 'Pierce|Janene|J|', 'de Caestecker|Christian|C|', 'Libes|Jaime|J|', 'Neblett|David|D|', 'de Caestecker|Mark|M|', 'Perantoni|Alan O|AO|', 'Tanigawa|Shunsuke|S|', 'Anderson|James R|JR|', 'Dome|Jeffrey S|JS|', 'Das|Amrita|A|', 'Carroll|Thomas J|TJ|', 'Lovvorn|Harold N|HN|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D015153:Blotting, Western D018797:Cell Cycle Proteins D002467:Cell Nucleus D049109:Cell Proliferation D002478:Cells, Cultured D002675:Child, Preschool D004622:Embryo, Mammalian D005260:Female D018507:Gene Expression Regulation, Developmental D006367:HeLa Cells D006801:Humans D007124:Immunoenzyme Techniques D007668:Kidney D007680:Kidney Neoplasms D008297:Male D051379:Mice D018345:Mice, Knockout D009399:Nephrons D010750:Phosphoproteins D010766:Phosphorylation D021381:Protein Transport D013234:Stem Cells D013347:Subcellular Fractions D014157:Transcription Factors D009396:Wilms Tumor D000091102:YAP-Signaling Proteins
Wilms tumor YAP1 nephrogenic rests biomarker anaplasia