Inhibition of transforming growth factor-β1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress

Julia Kirshner, Michael F. Jobling, Maria Jose Pajares, Shraddha A. Ravani, Adam B. Glick, Martin J. Lavin, Sergei Koslov, Yosef Shiloh, Mary Helen Barcellos-Hoff

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108 Scopus citations

Abstract

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor β (TGFβ)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGFβ inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgfβ1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGFβ type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced γH2AX radiation-induced foci; and increased radiosensitivity compared with TGFβ competent cells. We determined that loss of TGFβ signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGFβ restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgfβ1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGFβ may be used to advantage in cancer therapy.

Original languageEnglish (US)
Pages (from-to)10861-10869
Number of pages9
JournalCancer Research
Volume66
Issue number22
DOIs
StatePublished - Nov 15 2006

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Kirshner, J., Jobling, M. F., Pajares, M. J., Ravani, S. A., Glick, A. B., Lavin, M. J., Koslov, S., Shiloh, Y., & Barcellos-Hoff, M. H. (2006). Inhibition of transforming growth factor-β1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Research, 66(22), 10861-10869. https://doi.org/10.1158/0008-5472.CAN-06-2565