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.041416598
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发表时间：
2001-02-13
影响因子：
11.1
通讯作者：
Glazer, PW
中科院分区：
文献类型：
--
作者：
Peretz, S;Jensen, R;Glazer, PW
ATM 基因在共济失调性毛细血管扩张 (AT) 综合征中发生突变，与神经功能障碍、生长异常和极度放射敏感性相关。胰岛素样生长因子-I 受体 (ICF-IR) 是一种具有酪氨酸激酶活性的细胞表面受体，可以介导有丝分裂、细胞转化和细胞凋亡抑制。我们在此报告，与野生型细胞相比，AT 细胞表达低水平的 IGF-IR，并且显示出降低的 ICF-IR 启动子活性。 AT细胞与ATM cDNA的互补导致IGF-IR启动子活性增加和IGF-IR水平升高，而ATM显性失活片段在野生型细胞中的表达特异性降低IGF-IR表达，结果与ATM在转录水平上调节ICF-IR表达的作用一致。当通过异源病毒启动子在 AT 细胞中强制表达 IGF-IR cDNA 时，细胞就会获得接近正常的放射抗性。相反，在补充有 ATM cDNA 的 ATM 细胞中，IGF-IR 途径的特异性抑制会阻止放射敏感性的校正。总而言之，这些结果建立了 ATM 功能和 ICF-IR 表达之间的基本联系，并表明 ICF-IR 表达的减少有助于 AT 细胞的放射敏感性。此外，由于IGF-I在人体生长和代谢中发挥着重要作用，并作为发育神经组织的生存和分化因子，这些结果可能为理解AT综合征的其他方面，包括生长异常、胰岛素抵抗和神经变性提供基础。
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 (ICF-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 ICF-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 ICF-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 ICF-IR expression and suggest that reduced expression of ICF-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.