Regulation of the Atm promoter in vivo
Regulation of the Atm promoter in vivo
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DOI：
10.1002/gcc.20267
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发表时间：
2006-01-01
影响因子：
3.7
通讯作者：
Lavin, MF
中科院分区：
文献类型：
--
作者：
Gueven, N;Fukao, T;Lavin, MF
虽然ATM是人类遗传性疾病共济失调-毛细血管扩张症（A-T）中的蛋白质缺陷，主要是作为预先存在的蛋白质被辐射激活，但也有证据表明，该蛋白质的表达可以在转录水平上进行调节。电离辐射激活ATM启动子的报道仅在静止细胞培养。为了研究Atm启动子如何在体内调节，我们产生了在鼠Atm启动子控制下表达荧光素酶报告基因的转基因小鼠。使用生物光子成像系统在体内监测荧光素酶活性。在整个转基因动物中检测到强启动子活性，其中来自胸腺、腹部区域和生殖器官的信号特别高。这一活动进一步增加，电离辐射和热应力在时间依赖性的方式响应。荧光素酶活性，在体外测定提取物从不同的组织，表现出最高的活动，在睾丸，卵巢和小脑。这些小鼠接受单剂量的4戈伊全身辐射导致启动子的时间依赖性激活，在腹膜、皮肤和脾脏中观察到最强的反应。对于大多数组织测试，最大启动子活性达到辐射后8小时。观察到的启动子活性变化在很大程度上与组织提取物中Atm蛋白的水平和活性相关。这些结果表明，除了通过自磷酸化激活外，Atm还可以在体内在转录水平上进行调节，可能确保对辐射和其他刺激的更持续的响应。(c)2005年Wiley-Liss，Inc.
While ATM, the protein defective in the human genetic disorder ataxia-telangiectasia (A-T), is primarily activated as a preexisting protein by radiation, there is also evidence that expression of the protein can be regulated at the transcriptional level. Activation of the ATM promoter by ionizing radiation has been reported only in quiescent cells in culture. To investigate how the Atm promoter is regulated in vivo, we generated transgenic mice that express the luciferase reporter gene under the control of the murine Atm promoter. Using a biophotonic imaging system luciferase activity was monitored in vivo. Strong promoter activity was detected throughout the transgenic animals with particularly high signals from the thymus, abdominal region, and reproductive organs. This activity further increased in response to both ionizing radiation and heat stress in a time dependent manner. Luciferase activity, measured in vitro in extracts from different tissues, showed highest activities in testes, ovaries, and cerebellum. Subjecting these mice to a single dose of 4 Gy total body radiation led to a time-dependent activation of the promoter with the strongest response observed in the peritoneal membrane, skin, and spleen. For most tissues tested, maximal promoter activity was reached 8 hr after radiation. The observed changes in promoter activity largely correlated with levels and activity of Atm protein in tissue extracts. These results demonstrate that, in addition to activation by autophosphorylation, Atm can also be regulated in vivo at the transcriptional level possibly ensuring a more sustained response to radiation and other stimuli. (c) 2005 Wiley-Liss, Inc.