Protein Phosphatases and Proinflammatory Cytokines

描述(申请人提供)：蛋白磷酸酶4(PP4)是一种蛋白质 磷酸酶2A(PP2A)相关的丝氨酸/苏氨酸磷酸酶。PP2A参与调节多种细胞过程，如细胞信号、细胞周期 调控、细胞凋亡和肿瘤发生；然而，人们对此知之甚少 PP4的功能。为PP2A确定的上述许多功能都基于 这项研究使用了冈田酸，一种以前被认为是 PP2A是特异的，但现在已知在类似浓度下抑制PP4。 因此，以前确定的分配给PP2A的一些职能可能会 事实是PP4的功能。 PP4结合并激活Rel/NF-KB蛋白。Rel/NF-KB蛋白是关键蛋白 参与过多细胞反应的分子，如基因 调控，细胞凋亡，细胞周期，细胞增殖，肿瘤发生， 炎症和细胞黏附/迁移。我们最近的研究结果也表明 PP4激活cJun氨基末端激酶(JNK)。JNK亚群属于 丝裂原活化蛋白激酶(MAPK)超家族。JNK激酶级联是 参与细胞凋亡、分化、细胞增殖、肿瘤发生和 各种应激反应，如炎症反应和心脏 缺血/再灌流。理解PP4、AS的功能和调控 以及PP4激活核因子-KB/JNK的潜在机制将导致 对核因子-KB、JNK和PP4信号通路有更好的了解。具体的 目的如下：(1)研究PP4的调节和功能；(2)研究PP4的调节和功能 确定PP4在核因子-KB激活中的作用，以及(3)确定PP4在核因子-KB激活中的作用 PP4在JNK激活中的作用，本研究得出的信息应提供 更好地设计炎症性治疗药物的重要信息 疾病、癌症和心脏疾病。

DESCRIPTION (provided by applicant): Protein phosphatase 4 (PP4) is a protein phosphatase 2A (PP2A)-related serine/threonine phosphatase. PP2A is involved in regulating diverse cellular processes such as cell signaling, cell cycle regulation, apoptosis, and tumorigenesis; however, little is known about the functions of PP4. Many of the above functions identified for PP2A were based on the studies using okadaic acid, an inhibitor previously thought to be PP2A-specific, but now known to inhibit PP4 at similar concentrations. Therefore, some of the previously identified functions assigned to PP2A may in fact be the functions for PP4. PP4 binds to and activates Rel/NF-KB proteins. Rel/NF-KB proteins are pivotal molecules that are involved in a plethora of cellular responses such as gene regulation, apoptosis, cell cycle, cell proliferation, oncogenesis, inflammation, and cell adhesion/migration. Our recent results also indicate that PP4 activates cJun N-terminal kinase (JNK). JNK subgroup belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK kinase cascade is involved in apoptosis, differentiation, cell proliferation, oncogenesis, and various stress responses such as inflammatory responses and heart ischemia/reperfusion. Understanding the functions and regulation of PP4, as well as the underlying mechanisms of NF-KB/JNK activation by PP4 will lead to a better understanding of the NF-KB, JNK and PP4 signaling pathways. The specific aims are the following: (1) to study the regulation andfunction of PP4, (2) to determine the role of PP4 in NF-KB activation, and (3) to determine the role of PP4 in JNK activation, The information derived from this study should provide important information for a better design of therapeutic drugs for inflammatory diseases, cancers, and cardiac diseases.