Regulation Of JNK Signaling Pathway Research Articles

The involvement of PDIA2 gene in the progression of renal cell carcinoma is potentially through regulation of JNK signaling pathway.

Renal cell carcinoma (RCC) with poor prognosis and high incidence rate is a common malignant disease. Current therapies could bring little benefit for the patients with advanced-stage RCC. PDIA2 is an isomerase responsible for protein folding and its role in cancer including RCC is under investigation. In this study, we found that PDIA2 was expressed much higher in RCC tissues than the control but the methylation level of PDIA2 promoter was lower based on the TCGA data. Patients with higher PDIA2 expression exerted worse survival. In clinical specimen, PDIA2 expression was correlated to patients' clinical factors such as TNM stage (I/II vs III/IV, p = 0.025) and tumor size (≤ 7cm vs > 7cm, p = 0.004). Moreover, K-M analysis showed that PDIA2 was associated with patients' survival in RCC. PDIA2 was expressed much higher in cancer cells A498 than 786-O than that in 293T cells. After PDIA2 was knocked down, cell proliferation, migration and invasion was potently inhibited. But cell apoptotic rate increased reversely. Furthermore, the efficacy of Sunitinib on RCC cells was strengthened after PDIA2 knockdown. In addition, knockdown of PDIA2 gene leaded to downregulation of levels of JNK1/2, phosphorylated JNK1/2, c-JUN, and Stat3. But this inhibition was partially released when JNK1/2 was overexpressed. In consistent, cell proliferation was also partially recovered. In summary, PDIA2 plays important role in progression of RCC and JNK signaling pathway might be regulated by PDIA2. This study suggests PDIA2 as a candidate target for therapy of RCC.

Sestrin protects Drosophila midgut from mercury chloride-induced damage by inhibiting oxidative stress and stimulating intestinal regeneration

Overproduction of the deleterious reactive oxygen species (ROS) is one of the major causes of mercury, a heavy metal with diverse applications and environmental presence, induced neuronal and gastrointestinal adversities in exposed organism including Drosophila melanogaster. Sestrin, an oxidative stress responsive gene, emerges as a novel player in the management of oxidative stress response. Due to limited information regarding the role of sestrin in mercury-induced gastrointestinal adversities, it was hypothesized that modulation of sestrin may improve the mercury-induced gastrointestinal adversities in Drosophila. Here, we fed Drosophila with 400 μM HgCl2 and found that sestrin transcriptional level was significantly increased in midguts. Sestrin knockdown in HgCl2-exposed midguts decreased survival rates and climbing ability of flies, and inhibited superoxide dismutase and glutathione-S-transferase activities of midgut epithelieum. Meanwhile, sestrin knockdown in midgut aggravated the HgCl2-induced disruption of intestinal organization by worsening ROS production and cell apoptosis. Immunohistochemical staining data revealed that sestrin knockdown inhibited intestinal stem cell division in HgCl2-exposed midguts. Furthermore, JNK signaling was found to mediated sestrin expression in midgut. Taken together, the study demonstrated that sestrin protects Drosophila midgut from HgCl2-induced oxidative damage by inhibiting ROS production and stimulating the tissue regeneration program under regulation of JNK signaling pathway. This work suggests therapeutic implications of sestrin against heavy metal-induced gastrointestinal adversities in mammals.

Regulation of JNK signaling pathway and RIPK3/AIF in necroptosis-mediated global cerebral ischemia/reperfusion injury in rats

Receptor-interacting protein kinase 3 (RIPK3) regulates a newly discovered cell death form called necroptosis. RIPK3 nuclear translocation and inflammatory factor release are involved in necroptosis after rat global cerebral ischemia/reperfusion (I/R) injury. The purpose of this study was to investigate the effects of interactions between the RIPK3 and apoptosis-inducing factor (AIF) necroptosis pathway and the JNK-mediated inflammatory pathway. Rats were subjected to 4-vessel occlusion and reperfusion injury. RIPK3 inhibitor GSK872, RIPk3 recombinant adeno-associated virus (rAAV) and JNK-specific inhibitor SP600125 were intracerebroventricular injected before I/R. Hippocampus CA1 tissue were obtained and RIPK3, AIF, p-JNK, IL-6 were determined by western blot analysis. The RIPK3 and AIF interaction were also analyzed by immunofluorescence and immunoprecipitation. The expression of endogenous RIPK3, AIF, p-JNK and IL-6 was increased in hippocampus CA1 in I/R group. In addition, RIPK3 was increased in both the total protein and nuclear protein. GSK872 administration reduced the number of neuron deaths and the expression of RIPK3, p-JNK and IL-6. GSK872 also improve the rat neurobehavior. While use RIPk3 rAAV treatment to overexpress RIPK3, it appeared lower neuron survival. Immunofluorescence staining demonstrated that RIPK3 and AIF formed as a novel complex in the cytoplasm first, and then nuclear translocation. GSK872 pretreatment decreased the number of RIPK3-positive cells and related to the generation of RIPK3-AIF complex in nuclear. Moreover, the production of inflammatory factors levels was found to be significantly elevated after I/R. We further use SP600125 to attenuate inflammation cascade. It not only inhibits the expression of inflammatory factors p-JNK and IL-6, but also inhibits RIPK3 and AIF in the cytoplasm. Collectively, the results of our study indicate that RIPK3-mediated necroptosis interacts with the JNK-mediated inflammatory signaling pathway to participate in global cerebral I/R injury. JNK-regulated inflammatory mediators may promote the necroptosis initiation.

Green Pepper (Piper nigrum L.) Extract Suppresses Oxidative Stress and LPS-Induced Inflammation via Regulation of JNK Signaling Pathways

In this study, we compared the physicochemical properties and the antioxidant capacities of black and green pepper. Green pepper from India (GPI) and Sri Lanka (GPS) had higher Hunter L* and b* values and lower a* values than black pepper from India (BPI) and Sri Lanka (BPS). The contents of chlorophyll a and b, flavonoids, and phenolic compounds in GPI and GPS were higher than those in BPI and BPS. The peppercorns showed the following decreasing order of 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging capacities: GPI > GPS > BPI > BPS. High-performance liquid chromatography showed that the highest piperine content was present in GPI (8613.27 ± 45.86 mg/100 g). We further investigated the anti-inflammatory capacity of the green pepper. GPS and GPI significantly suppressed lipopolysaccharide (LPS)-induced nitrite production and inducible nitric oxide synthase expression without being cytotoxic to RAW 264.7 cells. GPS and GPI also suppressed the LPS-induced phosphorylation of mitogen-activated protein kinases, but not p65. GPS had a higher inhibitory effect on LPS-induced c-Jun phosphorylation and translocation from the cytosol to the nucleus than GPI. Thus, the findings of our study suggest that green pepper has the potential to be an effective nutraceutical against oxidative and inflammatory stress.

The Regulation of JNK Signaling Pathways in Cell Death through the Interplay with Mitochondrial SAB and Upstream Post-Translational Effects.

c-Jun-N-terminal kinase (JNK) activity plays a critical role in modulating cell death, which depends on the level and duration of JNK activation. The kinase cascade from MAPkinase kinase kinase (MAP3K) to MAPkinase kinase (MAP2K) to MAPKinase (MAPK) can be regulated by a number of direct and indirect post-transcriptional modifications, including acetylation, ubiquitination, phosphorylation, and their reversals. Recently, a JNK-mitochondrial SH3-domain binding protein 5 (SH3BP5/SAB)-ROS activation loop has been elucidated, which is required to sustain JNK activity. Importantly, the level of SAB expression in the outer membrane of mitochondria is a major determinant of the set-point for sustained JNK activation. SAB is a docking protein and substrate for JNK, leading to an intramitochondrial signal transduction pathway, which impairs electron transport and promotes reactive oxygen species (ROS) release to sustain the MAPK cascade.

NOB1 silencing inhibits the growth and metastasis of laryngeal cancer cells through the regulation of JNK signaling pathway.

Nin one binding protein (NOB1) plays important roles in the synthesis and degradation of proteins, thus having effects on the cellular process. In the present study, the expression level of NOB1 in laryngeal cancer patients was detected by quantitative PCR and western blotting, and the effect of NOB1 on growth and metastasis of laryngeal cancer cells was explored. Silence of NOB1 was found to inhibit the proliferation of laryngeal cancer cells, arrest cell cycle and induce cell apoptosis. NOB1 silence was also found to inhibit the migration and invasion of laryngeal cancer cells and to downregulate the protein levels of matrix metalloproteinases (MMPs)-2 and MMP-9. Further mechanism study revealed that the JNK signaling pathway was involved in the function of NOB1. Our present results suggest that NOB1 plays an oncogenic role in laryngeal cancer cells through the regulation of JNK signaling pathway, and lays a theoretical foundation for further exploration of NOB1.

The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation

Current studies demonstrated that cell survival is determined by a balance among signaling cascades, including those that recruit the Akt and JNK pathways. In our present work, the relationship between Akt1 and JNK1/2 was evaluated after cerebral ischemia–reperfusion in the hippocampus in a four-vessel occlusion model of Sprague–Dawley rats. This paper was based on our present and previous studies. Firstly, Akt1 had one active peak during reperfusion following 15 min ischemia. Secondly, two peaks of JNK1/2 activation occurred during reperfusion, respectively. Thirdly, the phosphorylation of JNK substrates c-Jun and Bcl-2, and the activation of a key protease of caspase-3 were detected. They only had one active peak, respectively, during reperfusion. To clarify the mechanism of Akt1 activation and further define whether JNK1/2 activation could be regulated by Akt1 through PI3K pathway, LY294002 and insulin were, respectively, administrated to the rats prior to ischemia. Our research indicated that LY294002, a PI3K inhibitor, significantly suppressed Akt1 activation. Furthermore, LY294002 significantly strengthened both peaks of JNK1/2 activation, c-Jun activation, Bcl-2 phosphorylation, and the activation of caspase-3 during reperfusion. In contrast, insulin, a PI3K agonist, not only obviously activated Akt1 during early and later reperfusion, but also inhibited phosphorylation of JNK1/2, c-Jun, and Bcl-2 and attenuated the activation of caspase-3. In addition, pretreatment of insulin significantly increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion. Consequently, our results indicated that the cross-talk between Akt1 and JNK1/2 could be mediated by insulin receptor through PI3K in rat hippocampus during reperfusion. This signaling pathway might play a neuroprotective role against ischemic insults via inhibition of the JNK pathway, involving the death effector of caspase-3.