Regulation of Necroptosis and inflammation

坏死性凋亡和炎症的调节

• 批准号: 10534748
• 负责人: Zhenkun Lou
• 金额: $ 35.64万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534748
• 关键词: 5' -AMP-activated protein kinase; 6p25; Affect; Apoptosis; Autophagocytosis; Cell Death; Cell physiology; Cells; Chromosome Mapping; Colon; Colon Carcinoma; Colorectal Cancer; Complex; Development; Disease; Future; Glioblastoma; Homeostasis; Hyperplasia; Inflammation; Inflammatory Bowel Diseases; Knockout Mice; Link; Malignant Neoplasms; Malignant neoplasm of lung; Mus; Mutation; Necrosis; PARK2 gene; Parkin; Parkinson Disease; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Polyps; Protein Kinase; RIPK1 gene; RIPK3 gene; Regulation; Role; Testing; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitination; autosome; cancer prevention; cell type; detection of nutrient; early onset; in vivo; intestinal epithelium; malignant breast neoplasm; novel; response; tumor; tumor initiation; tumor progression; tumorigenesis; ubiquitin-protein ligase

Abstract The term programmed necrosis or necroptosis has been used to distinguish several types of cell death such as apoptosis, autophagy, and pyroptosis. Necroptosis has been linked to inflammation response and diseases, which is a contributing factor for tumor initiation and progression. The protein kinase RIP1 and RIP3 are critical for the activation of necroptosis. Many studies have shown a complex functional interplay between RIP1 and RIP3 in regulating necrosome formation and necroptosis. Misregulation of this pathway would trigger abnormal tissue homeostasis, inflammation response, and caner initiation or progression. For example, abnormal RIP3-induced necroptosis in intestinal epithelium cause inflammatory bowel disease, which is linked to the development of colorectal cancer. Although RIP3 is a crucial kinase in necroptosis, how RIP3 is regulated in cells is not clear. We recently found that Parkin regulates RIP3 during necroptosis. Parkin is an E3 ubiquitin ligase that is encoded by the PARK2 gene. Mutation in the PARK2 gene is the most frequent cause of autosomal recessive early onset of Parkinson's Disease (PD). Emerging evidence suggests that Parkin also functions as a tumor suppressor, although how Parkin functions as a tumor suppressor remains unclear. Recently, we found that Parkin is a negative regulator of necroptosis and inflammation. Parkin promotes RIP3 ubiquitination, inhibits RIP3 phosphorylation, necrosome formation, and necroptosis in various cells. Conversely, deletion of the Parkin gene results in increased necroptosis. Importantly, deletion of the Park2 gene promotes inflammation and hyperplasia in vivo. Interestingly, we also found that Parkin itself is regulated by AMP-activated protein kinase (AMPK). Based on these preliminary results, we hypothesize that the AMPK-Parkin pathway is an important negative regulator of RIP3 by promoting RIP3 ubiquitination and inactivation. Further, the AMPK-Parkin-RIP3 pathway suppresses inflammation-induced tumorigenesis. To test this hypothesis, we propose the following Specific Aims: 1. To study the role of Parkin in RIP3 regulation and necroptosis; 2. To study the regulation of Parkin by AMPK; 3. To study the role of Parkin in inflammation and cancer. These studies will reveal a novel role of Parkin in the regulation of RIP3, necroptosis, and inflammation. In addition, a new mechanism by which Parkin functions as a tumor suppressor will be revealed. Accordingly, these studies will have a high impact for cancer pathogenesis and future cancer prevention. !

摘要 术语程序性坏死或坏死性凋亡已被用来区分几种类型的细胞死亡 如凋亡、自噬和焦亡。坏死性下垂与炎症反应有关， 疾病，这是肿瘤发生和发展的一个促成因素。蛋白激酶RIP 1和RIP 3 是激活坏死性凋亡的关键许多研究表明， RIP 1和RIP 3调节坏死体形成和坏死性凋亡。这条通路的失调会引发 异常的组织稳态、炎症反应和癌症的发生或发展。比如说， 异常RIP 3诱导的肠上皮坏死性凋亡导致炎症性肠病， 与结直肠癌的发展有密切关系。虽然RIP 3是坏死性凋亡中的关键激酶，但RIP 3是如何在细胞凋亡中发挥作用的呢？ 在细胞中的调控尚不清楚。我们最近发现帕金在坏死性凋亡过程中调节RIP 3。帕金是一个 由PARK 2基因编码的E3泛素连接酶。PARK 2基因突变是最常见的 常染色体隐性遗传帕金森病（PD）的早期发病的原因。新出现的证据表明 帕金也作为一种肿瘤抑制因子发挥作用，尽管帕金如何作为一种肿瘤抑制因子发挥作用仍然存在。 不清楚最近，我们发现Parkin是坏死性凋亡和炎症的负调节因子。帕金 促进RIP 3泛素化，抑制RIP 3磷酸化，坏死体形成和坏死性凋亡， 细胞相反，帕金基因的缺失导致坏死性凋亡增加。重要的是，删除 Park 2基因在体内促进炎症和增生。有趣的是，我们还发现帕金本身 由AMP激活的蛋白激酶（AMPK）调节。基于这些初步结果，我们假设， AMPK-Parkin通路通过促进RIP 3泛素化，是RIP 3的重要负调节因子 和失活。此外，AMPK-Parkin-RIP 3途径抑制炎症诱导的细胞凋亡。 肿瘤发生为了验证这一假设，我们提出了以下具体目标：1。研究帕金的角色 RIP 3调节和坏死性凋亡; 2.研究AMPK对Parkin的调节作用; 3.研究的作用 帕金在炎症和癌症。这些研究将揭示Parkin在RIP 3调节中的新作用， 坏死性凋亡和炎症。此外，帕金作为肿瘤发挥作用的一种新机制 抑制剂将被发现。因此，这些研究将对癌症发病机制产生很大影响， 未来的癌症预防 !