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Coordinate transcriptional and translational repression of p53 by TGF-β1 impairs the stress response

Fernando J López-Díaz1, Philippe Gascard, Sri Kripa Balakrishnan

  • 1Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Molecular Cell
|May 28, 2013
PubMed

Insights

Transforming growth factor-beta 1 (TGF-β1) signaling suppresses the cellular stress response by reducing p53 levels. This crosstalk between TGF-β1 and p53 pathways enhances drug resistance in precancerous cells.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Cellular stress profoundly alters RNA and protein synthesis.
  • The integration of intrinsic stress responses with extracellular signals is not well understood.
  • The p53 protein is a central regulator of the cellular stress response.

Purpose of the Study:

  • To investigate how transforming growth factor-beta 1 (TGF-β1) signaling interacts with the p53-centered cellular stress response.
  • To elucidate the mechanisms by which TGF-β1 interferes with p53 levels and function.
  • To determine the implications of this crosstalk for precancerous cells and drug resistance.

Main Methods:

  • Analysis of transcriptional and translational regulation of p53.
  • Investigation of protein-protein interactions involving E2F-4, Smads, p107, RPL26, and eEF1A.
  • Assessment of p53-activated transcription and apoptosis induction.
  • Evaluation of TGF-β1 signaling dominance over stress-induced pathways.

Main Results:

  • TGF-β1 signaling represses both transcription and translation of p53.
  • E2F-4 and Smad proteins form a complex that represses TP53 gene transcription.
  • TGF-β1 disrupts the association of RPL26 and eEF1A with p53 mRNA, inhibiting translation.
  • TGF-β1 signaling overrides stress-induced p53 responses and promotes drug resistance.

Conclusions:

  • Crosstalk between TGF-β1 and p53 pathways represents a critical regulatory node in cellular stress response.
  • This interaction leads to reduced p53 activity and apoptosis in precancerous cells.
  • The interplay between these pathways contributes to enhanced drug resistance.

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