Inhibition of transforming growth factor-β1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress
Inhibition of transforming growth factor-β1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress
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DOI：
10.1158/0008-5472.can-06-2565
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发表时间：
2006-11-15
期刊：
影响因子：
11.2
通讯作者：
Barcellos-Hoff, Mary Helen
中科院分区：
文献类型：
--
作者：
Kirshner, Julia;Jobling, Michael F.;Barcellos-Hoff, Mary Helen
电离辐射引起DNA损伤，从而激发由共济失调毛细血管扩张突变蛋白（ATM）的激酶活性协调的损伤控制细胞程序。转化生长因子β（TGF β）-1，它被辐射激活，是生理和病理过程的一种有效和多效性介质。在这里，我们表明，TGF β抑制阻碍典型的细胞DNA损伤应激反应。与TGF β感受态细胞相比，用TGF β I型受体激酶的小分子抑制剂处理的经辐照的TGF β 1指甲鼠上皮细胞或人上皮细胞表现出Chk 2、Rad 17和p53的磷酸化降低; γ H2 AX辐射诱导的病灶减少;以及放射敏感性增加。我们确定，上皮细胞中TGF β信号传导的缺失会截断ATM自磷酸化，并显著降低其激酶活性，而不影响蛋白质丰度。添加TGF β恢复功能性ATM和下游DNA损伤反应。这些数据揭示了微环境和ATM之间迄今未被发现的关键联系，ATM指导上皮细胞应激反应、细胞命运和组织完整性。因此，TGF β 1，除了其在同源生长控制中的作用，在调节对遗传毒性应激的反应中起着复杂的作用，其失败将有助于癌症的发展;相反，抑制TGF β可用于癌症治疗。
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 (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail 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 with 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, which 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.