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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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

Published on: August 4, 2019

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Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response

Mei Zhao1, Tianxiao Wang1,2, Frederico O Gleber-Netto1

  • 1Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Nature Communications
|January 3, 2024
PubMed

Insights

Mutant p53 proteins gain cancer-promoting functions by targeting MCMs, causing replication stress and DNA responses. This promotes tumor metastasis and an immunosuppressive microenvironment, impacting cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • TP53 mutations can lead to loss of p53 function and oncogenic gain-of-function (GOF) in mutant p53 (mutp53) proteins.
  • While GOF activities of TP53 mutations are known, the underlying mechanisms are not well understood.

Purpose of the Study:

  • To investigate the mechanisms by which GOF mutp53 promotes tumor development and progression.
  • To identify the molecular players and signaling pathways involved in mutp53-driven oncogenesis.

Main Methods:

  • Analysis of the mutp53 interactome.
  • Investigating the targeting of minichromosome maintenance complex (MCM) components by GOF mutp53.
  • Studying the resulting replication stress, chromosomal instability (CIN), and cytosolic DNA response.
  • Examining the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling.
  • Assessing the impact on tumor cell metastasis and the tumor microenvironment.

Main Results:

  • GOF mutp53 targets MCMs, leading to replication stress and CIN.
  • This triggers a cGAS-STING-dependent cytosolic DNA response.
  • The signaling cascade activates NC-NF-κB, promoting metastasis and an immunosuppressive tumor microenvironment by antagonizing interferon signaling.

Conclusions:

  • GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling is a key mechanism driving tumor progression.
  • This pathway contributes to metastasis and immune evasion.
  • Understanding these mechanisms offers insights into the role of p53 inactivation in cancer and potential therapeutic strategies.

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