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Related Experiment Video

Updated: May 31, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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DNA Damage-Induced Ferroptosis: A Boolean Model Regulating p53 and Non-Coding RNAs in Drug Resistance.

Shantanu Gupta1, Daner A Silveira2, José Carlos M Mombach3

  • 1Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, São Paulo 05508-090, SP, Brazil.

Proteomes
|January 23, 2025
PubMed
Summary

The tumor suppressor p53 regulates cell death pathways like ferroptosis and apoptosis. This study models how p53 proteoforms and non-coding RNAs influence these processes, offering new therapeutic strategies for cancer drug resistance.

Keywords:
CricRNA NOTCH1apoptosisferroptosislncRNA MALAT1miR-34c-5pp53

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Area of Science:

  • Cellular Biology
  • Cancer Research
  • Systems Biology

Background:

  • Wild-type p53 is crucial for cellular homeostasis and DNA damage response (DDR), regulating senescence, apoptosis, and autophagy.
  • Emerging evidence indicates p53's role in ferroptosis, an iron-dependent cell death pathway.
  • Post-translational modifications create p53 proteoforms, expanding its regulatory functions.

Purpose of the Study:

  • To elucidate the influence of p53 proteoforms and non-coding RNAs (ncRNAs) on ferroptosis, apoptosis, and senescence within the DDR.
  • To develop the first dynamic Boolean model integrating these molecular players in cancer cell death.
  • To identify potential therapeutic targets for overcoming drug resistance.

Main Methods:

  • Development of a dynamic Boolean model to simulate molecular interactions.
  • In silico analysis of p53 proteoforms, ncRNAs (CricNOTCH1, MALAT1), miR-34c-5p, Myc, and xCT.
  • Validation using gain- and loss-of-function perturbations and comparison with experimental data.

Main Results:

  • The model accurately reflects experimental observations in oral squamous cell carcinoma, nasopharyngeal carcinoma, and osteosarcoma.
  • Identified key positive feedback loops: CricNOTCH1/miR-34c/Myc, MALAT1/miR-34c/Myc, and Myc/xCT.
  • Demonstrated the critical role of cystine/glutamate transporter (xCT) in ferroptosis regulation.

Conclusions:

  • p53 proteoforms and specific ncRNAs significantly modulate ferroptosis, apoptosis, and senescence.
  • The developed model provides a systems-level understanding of DDR and cell death pathways.
  • Targeting p53 proteoforms and ncRNAs presents a promising strategy to combat cancer drug resistance and induce cell death.