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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

The Wilms tumor suppressor-1 target gene podocalyxin is transcriptionally repressed by p53

Patricia Stanhope-Baker1, Patricia M Kessler, Wenliang Li

  • 1Departments of Cancer Biology and Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

The Journal of Biological Chemistry
|May 25, 2004
PubMed

Insights

Restoring wild-type p53 function in Wilms tumor cells with CP-31398 activated p53 targets and repressed podocalyxin (PODXL). This suggests PODXL

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Wilms tumors exhibit diverse genetic alterations affecting tumor suppressors like WT1 and p53.
  • The specific downstream targets of WT1 and p53 in Wilms tumorigenesis remain largely undefined.
  • The anaplastic Wilms tumor cell line WiT49 harbors wild-type WT1 and mutant p53, and is treatment-refractory.

Purpose of the Study:

  • To investigate the functional restoration of mutant p53 in WiT49 cells using the small molecule CP-31398.
  • To identify p53-regulated genes involved in Wilms tumorigenesis.
  • To elucidate the regulatory relationship between WT1, p53, and the podocalyxin (PODXL) gene.

Main Methods:

  • Utilized the small molecule CP-31398 to restore wild-type p53 function in WiT49 cells.
  • Assessed p53-regulated promoter activity and UV-induced apoptosis.
  • Performed gene expression profiling to identify p53 target genes.
  • Investigated the in vivo binding of p53 to promoter sequences.

Main Results:

  • CP-31398 treatment reactivated p53-regulated transcription and enhanced UV-induced apoptosis in WiT49 cells.
  • Restored p53 binding to target gene promoters in vivo.
  • Gene expression profiling identified genes up- or down-regulated by p53.
  • Podocalyxin (PODXL) was identified as a key target gene repressed by p53 and positively regulated by WT1.

Conclusions:

  • CP-31398 effectively restores wild-type p53 activity in a mutant p53 Wilms tumor cell line.
  • PODXL is a direct transcriptional target of p53-mediated repression and WT1-mediated activation.
  • Aberrant PODXL expression, driven by altered WT1 and p53 pathways, may contribute to Wilms tumor development.

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