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Ubiquitin-proteasome system in the molecular mechanisms of lung injury and pulmonary fibrosis

泛素-蛋白酶体系统在肺损伤和肺纤维化分子机制中的作用

基本信息

批准号：
13670604
负责人：
KUWANO Kazuyoshi
金额：
$ 2.5万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670604/
关键词：
ubiquitin proteasome lung injury pulmonary fibrosis apoptosis p53 MDM2 SUMO1

项目摘要

Ubiquitin-proteasome system in lung injury and fibrosisUbiquitin and multiubiquitin were upregulated in lung tissues from patients with idiopathic pulmonary fibrosis (IPF). There were apoptotic epithelial cells in lung tissues from IPF. Multiubiquitin was detected in lung epithelial cells of bleomycin-induced pulmonary fibrosis in mice. Proteasome inhibitor induced apoptosis in lung epithelia cells in vitro, in which multiubiquitin was detected in apoptotic cells. Multiubiquitin was also detected by western blot analysis. These results suggest that epithelial cell apoptosis is involved in lung injury and pulmonary fibrosis in mouse and human, and that malfunction of ubiquitin-proteasome system may be involved in this apoptosis.The interaction of p53, MDM2, and SUMO1 in lung injury and fibrosisThe expression of p53, MDM2, and SUMO1 were upregulated in lung epithelial cells from patients with IPF and from bleomycin-induced pulmonary fibrosis in mice. The upregulation of these proteins were also detected by western blot analysis. MDM2 is E3 ligase for p53 and degenerate through ubiqutination. SUMO1 regulates self-ubiquitination of MDM2. We found that p53, MDM2 and SUMO1 interact each other and degrade through ubiquitin-proteasome system in lung epithelia cells. Ubiquitin-proteasome system is involved in p53-induced apoptosis of lung epithelial cells.

泛素-蛋白酶体系统在肺损伤和纤维化中的作用特发性肺纤维化（IPF）患者肺组织中泛素和多泛素表达上调。IPF肺组织中存在上皮细胞凋亡。博莱霉素诱导的小鼠肺纤维化模型肺上皮细胞中检测到多泛素。蛋白酶体抑制剂可诱导肺上皮细胞凋亡，凋亡细胞中可检测到多泛素。蛋白质印迹分析也检测到多泛素。这些结果表明，上皮细胞凋亡参与了小鼠和人肺损伤和肺纤维化的发生，泛素-蛋白酶体系统的功能障碍可能参与了这种凋亡，p53、MDM 2和SUMO 1在肺损伤和肺纤维化中的相互作用，和SUMO 1在来自IPF患者和来自博莱霉素诱导的小鼠肺纤维化的肺上皮细胞中上调。蛋白质印迹分析也检测到这些蛋白质的上调。MDM 2是p53的E3连接酶，并通过泛素化而退化。SUMO 1调节MDM 2的自我泛素化。我们发现，在肺上皮细胞中，p53、MDM 2和SUMO 1相互作用，通过泛素-蛋白酶体系统降解。泛素-蛋白酶体系统参与p53诱导的肺上皮细胞凋亡。