Functional Role of Nuclear Epidermal Growth Receptor (nEGFR) in Response to Irradiation

表皮生长因子受体(EGFR)在许多实体肿瘤中高表达，并与治疗耐药有关。最近的数据表明，EGFR在细胞应激反应的DNA修复过程中起着至关重要的作用。因此，基于放射肿瘤EGFR的干预策略意图增加未修复的双链断裂的数量，以诱导细胞死亡。我们可以看到，核内的EGFR参与了异染色质DNA双链断裂的修复。核EGFR调节Tip60乙酰转移酶的活性，这是组蛋白H3乙酰化所必需的。H3乙酰化触发染色质结构的开放，使DNA修复过程成为可能。我们研究的目的是了解Erbitux治疗对辐射反应中EGFR依赖的染色质重构的影响，这也可能解释Erbitux的耐药性。Src抑制剂Dasatinib或T654适配子对核EGFR转运的阻断与DNA修复的抑制有关，将在异种移植模型的动物研究中进行研究。应该阐明核EGFR对Tip60活性调节的关键作用，并将调查对遗传毒性治疗的干扰，如顺铂或乳头状瘤病毒的E6蛋白。最后，为了更好地理解EGFR在细胞应激管理中的作用，将讨论EGFR在线粒体活性调节中的作用。

The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors and is associated with treatment resistance. Recent data suggest, that the EGFR plays a crucial role during regulation of DNA-repair processes in response to cellular stress exposure. Consequently, radio-oncological EGFR based intervention strategies intent to increase the amount of unrepaired double strand breaks, to induce cell death. As we could show, nuclear EGFR is involved in repair of double strand breaks within heterochromatic DNA. Nuclear EGFR regulates activity of TIP60 acetyltransferase, which is needed for acetylation of histone H3. H3 acetylation triggers opening of chromatin structure to enable DNA-repair processes. Aim of our study is to understand the effect of Erbitux treatment on EGFR dependent chromatin remodeling in response to irradiation, which may also elucidate Erbitux resistance. Blockage of nuclear EGFR transport by src-inhibitor Dasatinib or T654 aptamer, which are associated with inhibition of DNA-repair, will be investigated in animal studies with xenocraft models. The crucial role of TIP60 activity regulation by nuclear EGFR should be elucidated and the interference with genotoxic treatments, e.g. cisplatin or the E6 protein of papilloma viruses will be investigated. Finally, the question of the role of EGFR during regulation of mitochondrial activity in response to irradiation will be addressed, to better understand the function of EGFR within cellular stress management.