Inhibition of TGFbeta1 Signaling Attenutates ATM Activity inResponse to Genotoxic Stress
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.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director. Office of Science. Office of AdvancedScientific Computing Research. Office of Biological and EnvironmentalResearch; National Aeronautics and Space Administration T6275-W, USDepartment of Defense DAMD17-01-0291
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 913158
- Report Number(s):
- LBNL-61740; CNREA8; R&D Project: 442301; BnR: KP1102020; TRN: US200802%%560
- Journal Information:
- Cancer Research, Vol. 66, Issue 22; Related Information: Journal Publication Date: November 15,2006; ISSN 0008-5472
- Country of Publication:
- United States
- Language:
- English
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