Inhibition of TGFbeta1 Signaling Attenutates ATM Activity inResponse to Genotoxic Stress

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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 {beta}1 (TGF{beta}), which is activated by radiation, is a potent and pleiotropic mediator of physiological and pathological processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}1 null murine epithelial cells or human epithelial cells treated with a small molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17 and p53, reduced {gamma}H2AX radiation-induced foci, and increased radiosensitivity compared to TGF{beta} competent ... continued below

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Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam B.; Lavin, Martin J. et al. September 15, 2006.

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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 {beta}1 (TGF{beta}), which is activated by radiation, is a potent and pleiotropic mediator of physiological and pathological processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}1 null murine epithelial cells or human epithelial cells treated with a small molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17 and p53, reduced {gamma}H2AX radiation-induced foci, and increased radiosensitivity compared to TGF{beta} competent cells. We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM that directs epithelial cell stress responses, cell fate and tissue integrity. Thus, TGF{beta}1, 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 TGF{beta} may be used to advantage in cancer therapy.

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  • Journal Name: Cancer Research; Journal Volume: 66; Journal Issue: 22; Related Information: Journal Publication Date: November 15,2006

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  • Report No.: LBNL--61740
  • Grant Number: DE-AC02-05CH11231
  • DOI: 10.1158/0008-5472.CAN-06-2565 | External Link
  • Office of Scientific & Technical Information Report Number: 913158
  • Archival Resource Key: ark:/67531/metadc887583

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  • September 15, 2006

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  • Sept. 22, 2016, 2:13 a.m.

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  • Sept. 29, 2016, 3:02 p.m.

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Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam B.; Lavin, Martin J. et al. Inhibition of TGFbeta1 Signaling Attenutates ATM Activity inResponse to Genotoxic Stress, article, September 15, 2006; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc887583/: accessed August 17, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.