Hsu Sheng-Chieh, Miller Stephanie A, Wang Yan, Hung Mien-Chie
Am J Transl Res. 2009 Mar 8;1(3):249-58.
The epidermal growth factor receptor (EGFR) has been shown to be able to translocate to the nucleus where it is involved in many cellular process including transcriptional regulation and DNA repair. Recently, it has been shown that the DNA damage-inducing agents ionizing radiation (IR) and cisplatin are able to induce EGFR nuclear localization, and this nuclear localization is correlated with increased DNA-PK activity, which plays an essential role in DNA double stranded repair. Here we sought to determine if there is a causal relationship between nuclear EGFR and DNA repair activity. We found that mutation in the nuclear localization signal (NLS) of EGFR (mNLS), known to be unable to translocate to the nucleus, released EGFR induced resistance to cisplatin. Re-introduction of an NLS in the C-terminal allowed EGFR to re-enter the nucleus and the cells regained resistance to cisplatin. In addition, we show that the re-expression of a functional nuclear localization sequence in EGFR (mNLS-R) is not only able to restore its resistance to cisplatin, but also reduced the DNA damage caused by cisplatin, and restored DNA repair activity. Thus, we demonstrate here that nuclear EGFR is required for DNA repair and resistance to cisplatin treatment.
表皮生长因子受体（EGFR）已被证明能够转运至细胞核，在包括转录调控和DNA修复在内的许多细胞过程中发挥作用。最近的研究表明，DNA损伤诱导剂电离辐射（IR）和顺铂能够诱导EGFR的核定位，而这种核定位与DNA-PK活性的增加相关，DNA-PK在DNA双链修复中起着至关重要的作用。在此，我们试图确定核EGFR与DNA修复活性之间是否存在因果关系。我们发现，已知无法转运至细胞核的EGFR核定位信号（NLS）突变（mNLS）可消除EGFR诱导的对顺铂的抗性。在C末端重新引入NLS可使EGFR重新进入细胞核，细胞也恢复了对顺铂的抗性。此外，我们还表明，在EGFR中重新表达功能性核定位序列（mNLS-R）不仅能够恢复其对顺铂的抗性，还能减少顺铂引起的DNA损伤，并恢复DNA修复活性。因此，我们在此证明，核EGFR是DNA修复和顺铂治疗抗性所必需的。
