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Inhibition of Transforming Growth Factor-ß1 Signaling Attenuates Ataxia Telangiectasia Mutated Activity in Response to Genotoxic Stress

¹ Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; ² Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland; ³ The Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland, Australia; and ⁴ Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel

Requests for reprints: Mary Helen Barcellos-Hoff, Life Sciences Division, Building 977, 1 Cyclotron Road, Berkeley, CA 94720. Phone: 510-486-6371; Fax: 510-495-2535; E-mail: mhbarcellos-hoff{at}lbl.gov.

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 ß (TGFß)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGFß inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgfß1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGFß type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced H2AX radiation-induced foci; and increased radiosensitivity compared with TGFß competent cells. We determined that loss of TGFß signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGFß 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, Tgfß1, 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 TGFß may be used to advantage in cancer therapy. (Cancer Res 2006; 66(22): 10861-9)

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