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Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.

Stephanie Halim1, Rebecca M Sebastian1, Kristi E Liivak1

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PubMed
Summary

Heat shock factor 1 (HSF1) activation supports cancer cell evolution by promoting beneficial p53 mutations. This proteostasis regulator reshapes the mutational landscape, aiding oncogenic mutations under drug pressure.

Keywords:
HSP70HSP90cancer evolutionchaperonesdeep mutational scanningheat shock factor Imutational bufferingp53protein foldingproteostasis

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Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Protein stability and folding are crucial for cellular function and are influenced by proteostasis networks.
  • Heat shock factor 1 (HSF1) is a key regulator of proteostasis, and its chronic upregulation is observed in cancer cells.
  • Upregulated proteostasis may enable cancer cells to acquire and maintain oncogenic mutations.

Purpose of the Study:

  • To investigate how HSF1 activation influences the mutational trajectories of p53.
  • To understand how HSF1 affects p53's ability to escape cytotoxic pressure induced by nutlin-3, an MDM2 inhibitor.

Main Methods:

  • Assessing the impact of HSF1 activation on p53 mutational escape.
  • Analyzing the fitness of dominant-negative p53 substitutions under HSF1 activation.
  • Examining specific amino acid changes within the p53 DNA-binding domain.

Main Results:

  • HSF1 activation significantly increases the fitness of dominant-negative p53 substitutions.
  • This effect is particularly pronounced for non-conservative, biophysically unfavorable mutations in buried regions of the p53 DNA-binding domain.
  • HSF1 activation preferentially supports the emergence and persistence of disruptive, cancer-associated p53 mutations.

Conclusions:

  • HSF1 activation reshapes the oncogenic mutational landscape.
  • It provides a selective advantage for biophysically disruptive p53 substitutions.
  • This links proteostasis network activity directly to cancer evolution and the maintenance of oncogenic mutations.