丝裂原激活蛋白激酶磷酸酶调控Nrf2信号通路的分子机制研究

转录因子NF-E2相关因子2（Nrf2）通过与抗氧化反应元件（antioxidant response element, ARE） 结合正向调控II相解毒酶基因、抗氧化酶基因及药物转运泵基因等靶基因的表达。最新研究发现在多种肿瘤细胞中Nrf2异常激活，促进肿瘤细胞的生长和耐药性，Nrf2被认为是新的癌基因和治疗癌症的新药靶，但其调控机制尚需深入研究。本课题组前期通过对非小细胞肺癌细胞株芯片分析发现丝裂原激活蛋白激酶磷酸酶（MKP-1） 调控Nrf2/ARE信号通路。本项目拟利用分子生物学等领域技术和手段，深入研究 MKP-1影响Nrf2稳定性及其转录活性的分子机制；并利用非小细胞肺癌细胞株、裸小鼠移植瘤模型和临床标本，离体及在体研究MKP1-Nrf2 这一新通路在肿瘤生长及耐药中的作用及相关机制。此项目将为探索治疗肿瘤的新途径提供理论基础。

The nuclear factor erythroid-2 related factor 2 （NRF2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that protect against oxidative and eletrophilic stress. Under normal condition, NRF2 is localized in the cytoplasm binding to Kelch-like ECH-associated protein 1 (KEAP1), which facilitates the degradation of NRF2 via the ubiquitin proteasome pathway. However, oxidants or electrophiles abrogates the interaction between KEAP1 with NRF2, resulting in increased nuclear accumulation of NRF2 and the transcriptional induction of target genes. Activation of NRF2 pathway is crucial for cancer chemoprevention. However, over-expression of NRF2 has been found in many types of cancer, facilitating tumor growth and resistance to anticancer therapy. Although a volume of work has been published regarding to the regulation of Nrf2 by Keap1, the mechanism leading to the abnormal Nrf2 activity in cancer cells are poorly characterized. Our group has a long standing interest in the regulation of Nrf2 signalling pathway. In our preliminary studies, we discovered that mitogen-activated protein kinase phosphatase-1 (MKP-1) regulates the Nrf2-ARE signaling pathway. Here in this proposal, we are planning to investigate the molecular mechanisms of MKP1 regulating Nrf2. Our study would establish a novel Nrf2 regulating mechanism, which is independent of Keap1. Our study might provide a novel approach of sensitizing tumour cells to anti-cancer drugs via inhibiting Nrf2.