Apoptosis Regulated by Fibronectin Signaling Pathways

改变的纤维连接蛋白基质，如在牙周病或炎症期间形成的 损害牙周膜(PDL)细胞功能。在炎症过程中，细菌 和宿主衍生的蛋白酶裂解细胞外基质(ECM)并释放 细胞外基质，包括纤维连接蛋白片段，进入炎症环境。我们已经证明，这些 碎片通过限制其增殖能力而对PDL细胞功能产生负面影响 趋化性，并通过诱导这些细胞中的程序性细胞死亡或凋亡。信令 触发这种细胞凋亡的机制是新的，需要转录 下调P53的表达。在P53的上游，粘着斑激酶的磷酸化和 C-Jun氨基末端激酶(JNK)1的磷酸化增加调节这一途径。此外， 然而，JNK1和JNK2在这一过程中相反地调节P53水平，其机制是 这种情况的发生尚不清楚。然而，理解这一机制对于理解 纤维连接蛋白基质环境改变的应激相关条件调节P53及其如何 大体上受到监管。已有报道表明，P53的JNK磷酸化可以稳定P53和 调节其转录活性。相反，JNK以p53泛素化和蛋白酶体为靶点 在非应激条件下，以MDM-2独立的方式降解。我们假设 JNK1和JNK2在纤维连接蛋白基质改变条件下相反调节P53和细胞凋亡 通过在转录水平上调节P53，通过泛素化和蛋白酶体降解， 独立于MDM-2。因此，JNK1和JNK2相反调节P53的机制 本研究将对纤维连接蛋白基质改变条件下的细胞凋亡进行研究。本研究 将扩大我们对严密调控关键调控因子P53的复杂机制的理解 应激激活的蛋白激酶JNK1对P53和细胞凋亡的特异性调控 和JNK2在改变的纤维连接蛋白基质条件下，与牙周炎有关。

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.