Activation of NF-κB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells
Activation of NF-κB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells
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DOI：
10.1073/pnas.95.10.5718
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发表时间：
1998-05-12
影响因子：
11.1
通讯作者：
Basbaum, C
中科院分区：
文献类型：
--
作者：
Li, JD;Feng, WJ;Basbaum, C
囊性纤维化（CF）是一种常染色体隐性遗传病，是白种人最常见的致死性遗传病，呼吸系统疾病是其发病和死亡的主要原因。事实上，95%的CF患者死于呼吸衰竭。铜绿假单胞菌是一种机会致病菌，长期感染超过85%的CF患者的肺部。它是抗生素不能根除的，并导致气道粘液过度产生，导致气道阻塞和死亡。这种病理学的分子机制尚不清楚。我们发现铜绿假单胞菌激活c-Src-Ras-MEK 1/2-MAPK-pp 90 rsk信号通路，导致核因子NF-κ B（p65/D50）的激活。活化的NF-κ B与MUC 2基因5 '侧翼区的κ B位点结合并活化MUC 2粘蛋白转录。这些研究为细菌-上皮相互作用带来了新的见解，更具体地说，为囊性纤维化的分子发病机制带来了新的见解，了解这些信号传导和基因调控机制为囊性纤维化开辟了新的治疗靶点。
Cystic fibrosis (CF) is an autosomal recessive disorder, the most common lethal genetic disease in Caucasians, Respiratory disease is the major cause of morbidity and mortality. Indeed, 95% of CF patients die of respiratory failure. Pseudomonas aeruginosa, an opportunistic pathogen, chronically infects the lungs of over 85% of CF patients. it is ineradicable by antibiotics and responsible for airway mucus overproduction that contributes to airway obstruction and death. The molecular mechanisms underlying this pathology are unknown. Here we show that P. aeruginosa activates a c-Src-Ras-MEK1/2-MAPK-pp90rsk signaling pathway that leads to activation of nuclear factor NF-kappa B (p65/D50). Activated NF-kappa B binds to a kappa B site in the 5'-flanking region of the MUC2 gene and activates MUC2 mucin transcription. These studies bring new insight into bacterial-epithelial interactions and more specifically into the molecular pathogenesis of cystic fibrosis, Understanding these signaling and gene regulatory mechanisms opens up new therapeutic targets for cystic fibrosis.