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Updated: Sep 12, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53
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A Quantitative High-Throughput Screen Identifies Compounds that Upregulate the p53 Isoform Δ133p53α and Inhibit

Delphine Lissa1, Sebastien M Joruiz1, Patricia K Dranchak2

  • 1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.

ACS Pharmacology & Translational Science
|August 4, 2025
PubMed
Summary
This summary is machine-generated.

Researchers developed a new assay to find compounds that boost Δ133p53α, a protein that combats cellular senescence. Two compounds, AZD1981 and celastrol, were identified, potentially offering new therapies for aging-related diseases.

Keywords:
AZD1981astrocytescelastrolchemical librariesp53 isoformsquantitative high-throughput screen

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Δ133p53α is a human/primate-specific p53 isoform that inhibits cellular senescence and the associated secretory phenotype (SASP).
  • Chaperone-assisted selective autophagy (CASA) is a key mechanism regulating Δ133p53α protein levels through degradation.
  • Cellular senescence is implicated in aging and age-related diseases.

Purpose of the Study:

  • To develop and implement a quantitative high-throughput screening (qHTS) assay to identify compounds that upregulate Δ133p53α protein levels.
  • To discover novel therapeutic agents for senescence- and aging-associated diseases by targeting Δ133p53α regulation.

Main Methods:

  • A novel cell-based qHTS assay using fluorescently labeled Δ133p53α was developed.
  • Over 10,000 small-molecule compounds were screened to identify modulators of Δ133p53α.
  • Candidate compounds were validated for their ability to upregulate endogenous Δ133p53α and reduce senescence markers.

Main Results:

  • The qHTS assay successfully profiled over 10,000 compounds.
  • Two compounds, AZD1981 and celastrol, were identified as potent inducers of Δ133p53α protein levels in human astrocytes and fibroblasts.
  • Celastrol's action is consistent with CASA-mediated regulation, involving heat shock protein 70 (HSP70) chaperones.
  • Upregulation of Δ133p53α led to reduced cellular senescence and SASP factor secretion.

Conclusions:

  • The developed qHTS assay is effective for identifying compounds that modulate Δ133p53α.
  • AZD1981 and celastrol show therapeutic potential for treating senescence- and aging-associated diseases.
  • Targeting Δ133p53α stabilization offers a promising strategy for developing novel anti-aging therapies.