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Aberrant activation, nuclear localization, and phosphorylation of Yes-associated protein-1 in the embryonic kidney and Wilms tumor.

Murphy AJ, Pierce J, de Caestecker C, Libes J, Neblett D, de Caestecker M, Perantoni AO, Tanigawa S, Anderson JR, Dome JS, Das A, Carroll TJ, Lovvorn HN
Pediatr Blood Cancer. 2014 61 (2): 198-205

PMID: 24115727 · PMCID: PMC3955491 · DOI:10.1002/pbc.24788

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.

© 2013 Wiley Periodicals, Inc.

MeSH Terms (25)

Adaptor Proteins, Signal Transducing Animals Blotting, Western Cell Nucleus Cell Proliferation Cells, Cultured Child, Preschool Embryo, Mammalian Female Gene Expression Regulation, Developmental HeLa Cells Humans Immunoenzyme Techniques Kidney Kidney Neoplasms Male Mice Mice, Knockout Nephrons Phosphoproteins Phosphorylation Protein Transport Stem Cells Subcellular Fractions Wilms Tumor

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