TY - JOUR
T1 - Inhibition of transforming growth factor-β1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress
AU - Kirshner, Julia
AU - Jobling, Michael F.
AU - Pajares, Maria Jose
AU - Ravani, Shraddha A.
AU - Glick, Adam B.
AU - Lavin, Martin J.
AU - Koslov, Sergei
AU - Shiloh, Yosef
AU - Barcellos-Hoff, Mary Helen
PY - 2006/11/15
Y1 - 2006/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-06-2565
DO - 10.1158/0008-5472.CAN-06-2565
M3 - Article
C2 - 17090522
AN - SCOPUS:33845303212
VL - 66
SP - 10861
EP - 10869
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 22
ER -