Apoptosis Regulated by Fibronectin Signaling Pathways

纤连蛋白信号通路调控细胞凋亡

• 批准号: 7654373
• 负责人: Yvonne L Kapila
• 金额: $ 4.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654373
• 关键词: Address; Apoptosis; Apoptosis Regulator; Apoptotic; Binding; Binding Sites; Catalytic Domain; Cell physiology; Cells; Chemotaxis; Cleaved cell; Condition; Data; Dominant-Negative Mutation; Down-Regulation; Endopeptidases; Environment; Extracellular Matrix; Fibronectins; Focal Adhesion Kinase 1; Genome; Goals; Hand; Individual; Induction of Apoptosis; Inflammation; Inflammatory; Investigation; MAPK8 gene; MAPK9 gene; Mediating; Messenger RNA; Mutate; Pathway interactions; Peptide Hydrolases; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phosphorylation; Phosphorylation Site; Phosphotransferases; Process; Protein Isoforms; Protein p53; Publishing; Regulation; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stress; TP53 gene; Transcriptional Regulation; Ubiquitination; insight; novel; programs; promoter; stress-activated protein kinase 1

Altered fibronectin matrices, as those elaborated during periodontal disease or inflammation compromise periodontal ligament (PDL)cell function. During the course of inflammation, bacterial and host-derived proteases cleave the extracellular matrix (ECM) and release fragments of the ECM, including fibronectin fragments, into the inflammatory milieu. We have shown that these fragments negatively influence PDL cell function by limiting their proliferative capacity and chemotaxis, and by inducing programmed cell death or apoptosis in these cells. The signaling mechanism by which this apoptosis is triggered is novel and requires the transcriptional downregulation of p53. Upstream of p53,decreases in focal adhesion kinase phosphorylation and increases in c-Jun N-terminal kinase (JNK)1 phosphorylation regulate this pathway. Furthermore, JNK1 and JNK2 oppositely regulate p53 levels in this process, however, the mechanism by which this occurs is not known. Yet, understanding this mechanism is critical to understanding how the stress-related condition of an altered fibronectin matrix environment regulates p53 and how p53 is regulated in general. Reports have shown that JNK phoshorylation of p53 can stabilize p53 and modulate its transcriptional activity. Conversely, JNK targets p53 for ubiquitination and proteasomal degradation in an Mdm-2 independent manner in nonstressed conditions. We hypothesize that JNK1 and JNK2 oppositely regulate p53 and apoptosis under altered fibronectin matrix conditions by modulating p53 at a transcriptional level and by ubiquitination and proteasomal degradation, independent of Mdm-2. Thus, the mechanism by which JNK1 and JNK2 oppositely regulate p53 and apoptosis under altered fibronectin matrix conditions will be examined in this study. This study will expand our understanding of the intricate mechanisms that tightly regulate p53,a key regulator of apoptosis, and of the specific modulation of p53 and apoptosis by stress-activated kinases,JNK1 and JNK2 under altered fibronectin matrix conditions which relate to periodontitis.

改变的纤维连接蛋白基质，如牙周病或炎症期间产生的纤维连接蛋白基质 损害牙周膜（PDL）细胞功能。在炎症过程中，细菌 并且宿主来源的蛋白酶切割细胞外基质（ECM）并释放ECM的片段。 ECM，包括纤连蛋白片段，进入炎症环境。我们已经证明， 片段通过限制其增殖能力而负面地影响PDL细胞功能， 趋化性，以及诱导这些细胞中的程序性细胞死亡或凋亡。信令 这种细胞凋亡的触发机制是新的，需要转录调控。 下调p53。在p53上游，粘着斑激酶磷酸化减少， c-Jun N-末端激酶（JNK）1磷酸化的增加调节该途径。此外，委员会认为， JNK 1和JNK 2在此过程中反向调节p53水平，然而， 这种情况的发生是未知的。然而，理解这种机制对于理解 纤连蛋白基质环境改变的应激相关条件调节p53以及p53是如何 一般来说，规范。报道显示p53的JNK磷酸化可以稳定p53， 调节其转录活性。相反，JNK靶向p53的泛素化和蛋白酶体 在非强制降解条件下以Mdm-2非依赖性方式降解。我们假设 JNK 1和JNK 2在纤连蛋白基质改变条件下反向调节p53和凋亡 通过在转录水平调节p53和通过泛素化和蛋白酶体降解， 独立于MDM-2。因此，JNK 1和JNK 2反向调节p53的机制 和在改变的纤连蛋白基质条件下的细胞凋亡将在本研究中进行检查。本研究 将扩大我们对紧密调节p53的复杂机制的理解，p53是一个关键的调节因子， 细胞凋亡，p53和细胞凋亡的特异性调节应激激活激酶，JNK 1 和JNK 2在与牙周炎相关的改变的纤连蛋白基质条件下的作用。