Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, University of Tübingen, Tübingen, Germany.
Division of Radiobiology and Molecular Environmental Research, Department of Radiooncology, Eberhard Karls University, Röntgenweg 11, 72076, Tübingen, Germany.
Strahlenther Onkol. 2010 Jan;186(1):1-6. doi: 10.1007/s00066-009-2026-4. Epub 2009 Dec 28.
Emerging evidence suggests the existence of a new mode of epidermal growth factor receptor (EGFR) signaling in which activated EGFR undergoes nuclear translocation following treatment with ionizing radiation. The authors provide evidence that the nuclear EGFR transport is a stress-specific cellular reaction, which is linked to src-dependent EGFR internalization into caveolae. These flask-shaped pits can fuse with endoplasmic reticulum and the EGFR is sorted into a perinuclear localization. This compartment may serve as a reservoir for nuclear EGFR transport which is regulated by PKCepsilon (protein kinase Cepsilon). Nuclear EGFR is able to induce transcription of genes essential for cell proliferation and cell-cycle regulation. Moreover, nuclear EGFR has physical contact with compounds of the DNA repair machinery and is involved in removal of DNA damage. Anti-EGFR strategies target radiation-associated EGFR nuclear translocation in different manners. EGFR-inhibitory antibodies, i.e., cetuximab (Erbitux((R))), can block nuclear translocation by EGFR immobilization within the cytosol in responder cell lines, whereas tyrosine kinase inhibitors rather target nuclear kinase activity of EGFR linked with cytosolic or nuclear functions. However, both strategies can inhibit DNA repair following irradiation.
新出现的证据表明，表皮生长因子受体 (EGFR) 存在一种新的信号转导模式，即 EGFR 在接受电离辐射后发生核转位。作者提供的证据表明，核 EGFR 转运是一种应激特异性的细胞反应，与Src 依赖性 EGFR 内化到 caveolae 有关。这些烧瓶状凹陷可与内质网融合，EGFR 被分类到核周定位。该隔室可作为核 EGFR 转运的储库，其受 PKCepsilon（蛋白激酶 Cepsilon）调节。核 EGFR 能够诱导对细胞增殖和细胞周期调控至关重要的基因的转录。此外，核 EGFR 与 DNA 修复机制的化合物具有物理接触，并参与 DNA 损伤的清除。抗 EGFR 策略以不同的方式靶向与辐射相关的 EGFR 核转位。EGFR 抑制性抗体，例如 cetuximab（Erbitux((R))），可以通过在应答细胞系中 EGFR 在细胞质内的固定来阻止核转位，而酪氨酸激酶抑制剂则针对与细胞质或核功能相关的 EGFR 核激酶活性。然而，这两种策略都可以抑制照射后的 DNA 修复。
