ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response.
ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response.
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DOI：
10.1073/pnas.98.4.1676
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发表时间：
2001-02
影响因子：
11.1
通讯作者：
S. Peretz;R. Jensen;R. Baserga;P. Glazer
中科院分区：
文献类型：
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作者：
S. Peretz;R. Jensen;R. Baserga;P. Glazer
ATM基因在共济失调毛细血管扩张综合征（AT）中发生突变，与神经功能障碍、生长异常和极端放射敏感性相关。胰岛素样生长因子-I受体（IGF-IR）是一种具有酪氨酸激酶活性的细胞表面受体，可介导有丝分裂、细胞转化和抑制凋亡。我们在这里报告，AT细胞表达低水平的IGF-IR和显示降低IGF-IR启动子活性与野生型细胞相比。AT细胞与ATM cDNA互补导致IGF-IR启动子活性增加和IGF-IR水平升高，而在野生型细胞中表达ATM的显性负性片段特异性降低IGF-IR表达，结果与ATM在转录水平上调节IGF-IR表达的作用一致。当IGF-IR cDNA的表达通过异源病毒启动子在AT细胞中被强制时，细胞被赋予接近正常的辐射抗性。相反，在ATM细胞中补充的ATM cDNA，特异性抑制IGF-IR途径阻止校正的放射敏感性。总之，这些结果建立了ATM功能和IGF-IR表达之间的基本联系，并表明IGF-IR的表达减少有助于AT细胞的放射敏感性。此外，由于IGF-I在人类生长和代谢中起着重要作用，并作为神经元组织发育的存活和分化因子，这些结果可能为理解AT综合征的其他方面提供基础，包括生长异常，胰岛素抵抗和神经变性。
The ATM gene is mutated in the syndrome of ataxia telangiectasia (AT), associated with neurologic dysfunction, growth abnormalities, and extreme radiosensitivity. Insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor with tyrosine kinase activity that can mediate mitogenesis, cell transformation, and inhibition of apoptosis. We report here that AT cells express low levels of IGF-IR and show decreased IGF-IR promoter activity compared with wild-type cells. Complementation of AT cells with the ATM cDNA results in increased IGF-IR promoter activity and elevated IGF-IR levels, whereas expression in wild-type cells of a dominant negative fragment of ATM specifically reduces IGF-IR expression, results consistent with a role for ATM in regulating IGF-IR expression at the level of transcription. When expression of IGF-IR cDNA is forced in AT cells via a heterologous viral promoter, near normal radioresistance is conferred on the cells. Conversely, in ATM cells complemented with the ATM cDNA, specific inhibition of the IGF-IR pathway prevents correction of the radiosensitivity. Taken together, these results establish a fundamental link between ATM function and IGF-IR expression and suggest that reduced expression of IGF-IR contributes to the radiosensitivity of AT cells. In addition, because IGF-I plays a major role in human growth and metabolism and serves as a survival and differentiation factor for developing neuronal tissue, these results may provide a basis for understanding other aspects of the AT syndrome, including the growth abnormalities, insulin resistance, and neurodegeneration.