Mechanism of IKK Signaling Network

IKK信号网络机制

• 批准号: 9042393
• 负责人: ANNING LIN
• 金额: $ 30.02万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-07 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042393
• 关键词: Apoptosis; Apoptotic; Autophagocytosis; BCL2 gene; Bad protein; Binding; Biological Process; Cell Death; Cell Survival; Cessation of life; Complex; Cytoplasm; Cytoplasmic Protein; Data; Glycolysis; Goals; Growth; Health; Immune response; In Vitro; Inflammation; Inflammatory; Inhibition of Apoptosis; Interleukin-3; Knock-in Mouse; Light; Mediating; Mitochondria; Modeling; Molecular; Molecular Probes; Mus; Necrosis; Phosphorylation; Phosphotransferases; Play; Prevention; Protein Family; Protein Kinase; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stimulus; TNF gene; Testing; Withdrawal; cell growth; cytokine; extracellular; human disease; in vivo; knock-down; mutant; novel; response; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby identifying potential therapeutic targets for prevention and treatment of human diseases. In this proposal, we will study the molecular mechanism underlying the IKK signaling network and its pathophysiological implications, using regulation of Bad by IKK in TNFα-induced apoptosis as a molecular probe. Using multifaceted approaches, we uncovered a second signaling pathway of the IKK signaling network, i.e., the IKK-Bad axis. We found that Bad is a novel target of IKK and is also required for TNFα-induced apoptosis in vitro and in vivo. Regulation of Bad by IKK is involved in inhibition of TNFα-induced apoptosis. We hypothesize that in addition to activation of NF-κB, IKK inhibits TNFα-induced apoptosis via inactivation of Bad, i.e., the "NF-κB activation and Bad inactivation" model. This proposal is novel, as it will study the role of the IKK-Bad axis in apoptosis induced by TNFα and other death stimuli, as well as in necrosis and autophagy, and the underlying mechanism and pathophysiological functions of the regulation in vitro and in vivo. This study will put forward a novel paradigm regarding the IKK signaling network and will provide a better understanding of the biological functions of the IKK signaling network in terms of regulation of cell death, which plays an important role in many human diseases.

描述（由适用提供）：我们研究的长期目标是研究如何响应特定的细胞外刺激，从而确定预防和治疗人类疾病的潜在治疗靶标。在此提案中，我们将研究IKK信号网络及其病理生理意义的分子机制，使用IKK在TNFα诱导的细胞凋亡中作为分子探针的调节。使用多方面方法，我们发现了IKK信号网络的第二个信号通路，即IKK-BAD轴。我们发现BAD是IKK的新靶标，也是TNFα诱导的体外和体内凋亡所必需的。 IKK对BAD的调节参与了TNFα诱导的凋亡的抑制。我们假设除了激活NF-κB外，IKK还通过失活的失活，即“ NF-κB激活和不良失活”模型抑制了TNFα诱导的凋亡。该建议是新颖的，因为它将研究IKK-BAD轴在TNFα和其他死亡刺激以及坏死和自噬中引起的凋亡中的作用，以及在体外和体内调节的基本机制和病理生理功能。这项研究将提出有关IKK信号网络的新型范式，并在调节细胞死亡方面更好地了解IKK信号网络的生物学功能，这在许多人类疾病中起着重要作用。

项目成果

Bacterial effector NleL promotes enterohemorrhagic E. coli-induced attaching and effacing lesions by ubiquitylating and inactivating JNK.

细菌效应器 NleL 通过泛素化和灭活 JNK 来促进肠出血性大肠杆菌诱导的附着和消除病变。

• DOI: 10.1371/journal.ppat.1006534
• 发表时间: 2017-07
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Sheng X;You Q;Zhu H;Chang Z;Li Q;Wang H;Wang C;Wang H;Hui L;Du C;Xie X;Zeng R;Lin A;Shi D;Ruan K;Yan J;Gao GF;Shao F;Hu R
• 通讯作者: Hu R

ATIA: a link between inflammation and hypoxia.

ATIA：炎症和缺氧之间的联系。

• DOI: 10.1016/j.molcel.2011.05.023
• 发表时间: 2011
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Lin,Anning