TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner

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Updated: Jul 18, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Shouting Zhang1, Maria Ekman, Noopur Thakur

  • 1Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Uppsala, Sweden.

Cell Cycle (Georgetown, Tex.)
|December 19, 2006
PubMed

Insights

Transforming growth factor-beta (TGFβ) induces apoptosis via ATM and p53 in epithelial cells. Smad7 acts as a scaffold protein, facilitating interactions between p38, ATM, and p53, protecting the genome from stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • ATM (Ataxia-telangiectasia mutated) and p53 are critical tumor suppressors involved in DNA damage response.
  • These proteins, along with gammaH2AX, act as guardians against DNA damage and are frequently inactivated in cancers.
  • Extracellular stress, such as that induced by TGFβ, can impact cellular integrity and genomic stability.

Purpose of the Study:

  • To investigate the functional cross-talk between TGFβ and the ATM/p53 pathway in epithelial cells.
  • To elucidate the role of Smad7 in mediating TGFβ-induced apoptosis and DNA damage response.
  • To understand how Smad7 facilitates interactions between key signaling molecules like p38 MAP kinase, ATM, and p53.

Main Methods:

  • Utilized ectopic expression of p53 and siRNA for Smad7.
  • Employed p38alpha-/- deficient cells and specific kinase inhibitors.
  • Investigated protein interactions, colocalization with gammaH2AX, and cell cycle checkpoint functions.

Main Results:

  • Demonstrated that TGF-beta induces apoptosis through the ATM and p53 pathways in epithelial cells.
  • Showed that Smad7 functions as a scaffold protein, promoting the activation of p38, ATM, and p53 upon TGFβ treatment.
  • Confirmed Smad7 colocalization with gammaH2AX in DNA damage foci and its necessity for cell cycle checkpoints.

Conclusions:

  • Smad7 plays a crucial role upstream of ATM and p53 in protecting the genome from extracellular stress.
  • The TGFβ-Smad7-p38-ATM-p53 axis is vital for maintaining genomic stability in epithelial cells.
  • Targeting this pathway could offer novel therapeutic strategies for cancers with inactivated ATM and p53.

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