Inhibition of Transforming Growth Factor-1 Signaling Attenuates Ataxia Telangiectasia Mutated Activity in Response to Genotoxic Stress

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

^* To whom correspondence should be addressed. E-mail: mhbarcellos-hoff{at}lbl.gov.

	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 (TGF)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced H2AX radiation-induced foci; and increased radiosensitivity compared with TGF competent cells. We determined that loss of TGF signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF 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, Tgf1, 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 may be used to advantage in cancer therapy. (Cancer Res 2006; 66(22): 10861-9)

Key Words: DNA damage, epithelial, cytokine

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