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. !

抽象的 编程的坏死或坏死术已用于区分几种类型的细胞死亡 例如凋亡，自噬和凋亡。坏死性与炎症反应有关， 疾病，这是导致肿瘤启动和进展的因素。蛋白激酶RIP1和RIP3 对于激活坏死性至关重要。许多研究表明，功能相互作用 RIP1和RIP3在调节坏死体形成和坏死。这条途径的不正体会触发 组织稳态异常，炎症反应以及罐头的起始或进展。例如， RIP3诱导的异常肠上皮上皮的坏死作用会引起炎症性肠病，这是连接的 结直肠癌的发展。尽管RIP3是坏死性的关键激酶，但RIP3是如何的 在细胞中受到调节尚不清楚。最近，我们发现帕金在坏死过程中调节RIP3。帕金是一个 由PARK2基因编码的E3泛素连接酶。 PARK2基因中的突变是最常见的 帕金森氏病（PD）的常染色体隐性病因。新兴证据表明 帕金还充当肿瘤抑制剂，尽管Parkin如何充当肿瘤抑制剂 不清楚。最近，我们发现帕金是坏死和炎症的负调节剂。帕金 在各种 细胞。相反，parkin基因的缺失导致坏死性增加。重要的是，删除 PARK2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是 由AMP激活的蛋白激酶（AMPK）调节。基于这些初步结果，我们假设 通过促进RIP3泛素化，AMPK-Parkin途径是RIP3的重要负调节剂 和灭活。此外，AMPK-Parkin-RIP3途径抑制了炎症引起的 肿瘤发生。为了检验这一假设，我们提出了以下特定目的：1。研究帕金的作用 在RIP3调节和坏死中； 2。研究AMPK对Parkin的调节； 3。研究 炎症和癌症中的帕金。这些研究将揭示帕金在RIP3调节中的新作用， 坏死性和炎症。另外，帕金充当肿瘤的新机制 抑制器将被揭示。因此，这些研究将对癌症的发病机理产生高影响 未来的预防癌症。 呢