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New tricks for an old fox: impact of TGFβ on the DNA damage response and genomic stability

Mary Helen Barcellos-Hoff1, Francis A Cucinotta2

  • 1Department of Radiation Oncology, New York University School of Medicine, 566 First Avenue, New York, NY 10016, USA. barcem01@nyumc.org francis.cucinotta@unlv.edu.

Science Signaling
|September 4, 2014
PubMed

Insights

Transforming growth factor-β (TGFβ) is crucial for tissue homeostasis and DNA damage response (DDR). Its depletion increases genomic instability, impacting cancer development and therapy response.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor-β (TGFβ) regulates cellular proliferation and tissue homeostasis.
  • TGFβ acts as a tumor suppressor in early carcinogenesis but a tumor promoter in established cancers.
  • Its role in maintaining genomic stability via the DNA damage response (DDR) is less understood.

Purpose of the Study:

  • To investigate the role of TGFβ in maintaining genomic stability through its participation in the DDR.
  • To understand the paradoxical roles of TGFβ in tumorigenesis.
  • To explore therapeutic implications for DNA damage-inducing therapies.

Main Methods:

  • Deletion of Tgfb1 in murine epithelium and depletion of TGFβ ligand or pathway inhibition in human epithelial cells.
  • Assessment of genomic instability (GIN) including gene amplification, aneuploidy, and centrosome aberrations.
  • Analysis of DNA damage response activation, focusing on ataxia telangiectasia mutated (ATM) kinase activity and SMAD transcription factors.

Main Results:

  • TGFβ depletion or signaling inhibition in epithelial cells increases genomic instability (GIN).
  • TGFβ depletion compromises cell survival after radiation and impairs DDR activation due to reduced ATM activity.
  • SMAD2 and SMAD7 are implicated in the DDR, interacting with ATM and TGFβ receptor type I.

Conclusions:

  • TGFβ plays a significant role in maintaining genomic stability by participating in the DDR.
  • Understanding TGFβ's function in DDR and GIN suppression is key to resolving its paradoxical roles in cancer.
  • This knowledge has therapeutic implications for enhancing DNA damage-inducing cancer therapies.

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