Journal articles: 'JNK'

1

Zhao, Yi, Giada Spigolon, Christophe Bonny, Juraj Culman, Alessandro Vercelli, and Thomas Herdegen. "The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria." Molecular and Cellular Neuroscience 49, no. 3 (March 2012): 300–310. http://dx.doi.org/10.1016/j.mcn.2011.12.005.

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Weitzman, Jonathan B. "JNK." Current Biology 10, no. 8 (April 2000): R290. http://dx.doi.org/10.1016/s0960-9822(00)00429-2.

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Chen, Wei-Kai, Yvonne Y. C. Yeap, and Marie A. Bogoyevitch. "The JNK1/JNK3 interactome – Contributions by the JNK3 unique N-terminus and JNK common docking site residues." Biochemical and Biophysical Research Communications 453, no. 3 (October 2014): 576–81. http://dx.doi.org/10.1016/j.bbrc.2014.09.122.

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4

Wong, W. "JNK Slowdown." Science Signaling 2, no. 78 (July 7, 2009): ec230-ec230. http://dx.doi.org/10.1126/scisignal.278ec230.

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Dempsey, Laurie A. "Macrophage Jnk." Nature Immunology 14, no. 2 (January 18, 2013): 118. http://dx.doi.org/10.1038/ni.2532.

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Okugawa, Shu, Yasuo Ota, Takatoshi Kitazawa, Kuniko Nakayama, Shintaro Yanagimoto, Kunihisa Tsukada, Miki Kawada, and Satoshi Kimura. "Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages." American Journal of Physiology-Cell Physiology 285, no. 2 (August 2003): C399—C408. http://dx.doi.org/10.1152/ajpcell.00026.2003.

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The mechanisms by which lipopolysaccharide (LPS) is recognized, and how such recognition leads to innate immune responses, are poorly understood. Stimulation with LPS induces the activation of a variety of proteins, including mitogen-activated protein kinases (MAPKs) and NF-κB. Activation of protein tyrosine kinases (PTKs) is also necessary for a number of biological responses to LPS. We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK). Both the JAK inhibitor AG490 and the kinase-deficient JAK2 protein reduce the phosphorylation of JNK and phosphatidylinositol 3-kinase (PI3K) via LPS stimulation. Pharmacological inhibition of the kinase activity of PI3K with LY-294002 decreases the phosphorylation of JNK. Finally, we show that JAK2 is involved in the production of IL-1β and IL-6. PI3K and JNK are also important for the production of IL-1β. These results suggest that LPS induces tyrosine phosphorylation of JAK2 via TLR4 and that JAK2 regulates phosphorylation of JNK mainly through activation of PI3K. Phosphorylation of JAK2 via LPS stimulation is important for the production of IL-1β via the PI3K/JNK cascade. Thus JAK2 plays a pivotal role in LPS-induced signaling in macrophages.

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Lan, K. P., C. J. Wang, J. D. Hsu, K. M. Chen, S. C. Lai, and H. H. Lee. "Induced eosinophilia and proliferation inAngiostrongylus cantonensis-infected mouse brain are associated with the induction of JAK/STAT1, IAP/NF-κB and MEKK1/JNK signals." Journal of Helminthology 78, no. 4 (December 2004): 311–17. http://dx.doi.org/10.1079/joh2004256.

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AbstractEosinophilic meningitis or meningoencephalitis caused byAngiostrongylus cantonensisis endemic to the Pacific area of Asia, especially Taiwan, Thailand, and Japan. Although eosinophilia is an important clinical manifestation ofA. cantonensisinfection, the role of eosinophils in the progress of the infection remains to be elucidated. In this experiment, we show thatA. cantonensis-induced eosinophilia and inflammation might lead to the induction of IAP/NF-κB, JAK/STAT1 and MEKK1/JNK signals. The phosphorylation levels of JAK and JNK, STAT1, IAP, NF-κB and MEKK1 protein products were significantly increased after 12 days or 15 days ofA. cantonensisinfection. However, no significant differences in MAPKs such as Raf, MEK-1, ERK1/2 and p38 expression were found between control and infected mice. The activation potency of JAK/STAT1, IAP/NF-κB and MEKK1/JNK started increasing on day 3, with significant induction on day 12 or day 15 afterA. cantonensisinfection. Consistent results were noted in the pathological observations, including eosinophilia, leukocyte infiltration, granulomatous reactions, and time responses in the brain tissues of infected mice. These data suggest that the development of brain injury by eosinophilia ofA. cantonensisinfection is associated with activation of JAK/STAT1 signals by cytokines, and/or activation of MEKK1/JNK by oxidant stress, and/or activation of NF-κB by increasing IAP expression.

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Nihalani, Deepak, Hetty N. Wong, and Lawrence B. Holzman. "Recruitment of JNK to JIP1 and JNK-dependent JIP1 Phosphorylation Regulates JNK Module Dynamics and Activation." Journal of Biological Chemistry 278, no. 31 (May 19, 2003): 28694–702. http://dx.doi.org/10.1074/jbc.m304212200.

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Sabapathy, Kanaga, Konrad Hochedlinger, Shin Yuen Nam, Anton Bauer, Michael Karin, and Erwin F. Wagner. "Distinct Roles for JNK1 and JNK2 in Regulating JNK Activity and c-Jun-Dependent Cell Proliferation." Molecular Cell 15, no. 5 (September 2004): 713–25. http://dx.doi.org/10.1016/j.molcel.2004.08.028.

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10

Borhani, David W. "Covalent JNK inhibitors?" Proceedings of the National Academy of Sciences 106, no. 8 (February 9, 2009): E18. http://dx.doi.org/10.1073/pnas.0812246106.

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11

Weitzman, Jonathan B. "JNK and obesity." Genome Biology 3 (2002): spotlight—20021121–01. http://dx.doi.org/10.1186/gb-spotlight-20021121-01.

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12

Barker, Ralph J., and Robert G. Gourdie. "JNK Bond Regulation." Circulation Research 91, no. 7 (October 4, 2002): 556–58. http://dx.doi.org/10.1161/01.res.0000036861.37203.2f.

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13

Leavy, Olive. "The JNK diet." Nature Reviews Immunology 7, no. 12 (December 2007): 918–19. http://dx.doi.org/10.1038/nri2226.

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14

Bae, Yoe-Sik, Ha Young Lee, Sun Young Lee, Sang Doo Kim, Hak Jung Kim, Young Su Jung, and Suk-Hwan Baek. "Sphingosylphosphorylcholine stimulates CCL2 production and ICAM expression from human umbilical vein endothelial cells (60.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 60.2. http://dx.doi.org/10.4049/jimmunol.186.supp.60.2.

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Abstract We investigated the functional role of sphingosylphosphorylcholine (SPC), a component of high density lipoprotein (HDL) particles, in human umbilical vein endothelial cells (HUVECs). SPC stimulation induced production of the CCL2 chemokine in a PTX-sensitive G-protein-dependent manner. SPC treatment caused the activation of NF-κB and AP-1, which are essential for SPC-induced CCL2 production, and also induced the activation of three MAPKs, ERK, p38 MAPK, and JNK. p38 MAPK or JNK by specific inhibitors caused a dramatic decrease in SPC-induced CCL2 production. The Jak/STAT3 pathway was also activated upon SPC stimulation of HUVECs. Pretreatment with a Jak inhibitor blocked not only SPC-induced p38 MAPK and JNK activation but also NF-κB and AP-1 activation. Our results suggest that SPC stimulates HUVECs, resulting in Jak/STAT3-, NF-κB-, and AP-1-mediated CCL2 production. We also observed that SPC stimulated expression of the adhesion molecule ICAM-1 in HUVECs. Taken together, we suggest that SPC may contribute to atherosclerosis; thus SPC and its as yet unidentified target receptor offer a starting point for the development of a treatment for atherosclerosis.

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Wang, Ziqian, Chenyue Zhan, Fang Zeng, and Shuizhu Wu. "A biopolymer-based and inflammation-responsive nanodrug for rheumatoid arthritis treatment via inhibiting JAK-STAT and JNK signalling pathways." Nanoscale 12, no. 45 (2020): 23013–27. http://dx.doi.org/10.1039/d0nr05551d.

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16

Eliopoulos, Aristides G., Elyse R. Waites, Sarah M. S. Blake, Clare Davies, Paul Murray, and Lawrence S. Young. "TRAF1 Is a Critical Regulator of JNK Signaling by the TRAF-Binding Domain of the Epstein-Barr Virus-Encoded Latent Infection Membrane Protein 1 but Not CD40." Journal of Virology 77, no. 2 (January 15, 2003): 1316–28. http://dx.doi.org/10.1128/jvi.77.2.1316-1328.2003.

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ABSTRACT The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner. As a result, LMP1 constitutively engages signaling pathways, such as the JNK and p38 mitogen-activated protein kinases (MAPK), the transcription factor NF-κB, and the JAK/STAT cascade, and these activities may explain many of its pleiotropic effects on cell phenotype, growth, and transformation. In this study we demonstrate the ability of the TRAF-binding domain of LMP1 to signal on the JNK/AP-1 axis in a cell type- dependent manner that critically involves TRAF1 and TRAF2. Thus, expression of this LMP1 domain in TRAF1-positive lymphoma cells promotes significant JNK activation, which is blocked by dominant-negative TRAF2 but not TRAF5. However, TRAF1 is absent in many established epithelial cell lines and primary nasopharyngeal carcinoma (NPC) biopsy specimens. In these cells, JNK activation by the TRAF-binding domain of LMP1 depends on the reconstitution of TRAF1 expression. The critical role of TRAF1 in the regulation of TRAF2-dependent JNK signaling is particular to the TRAF-binding domain of LMP1, since a homologous region in the cytoplasmic tail of CD40 or the TRADD-interacting domain of LMP1 signal on the JNK axis independently of TRAF1 status. These data further dissect the signaling components used by LMP1 and identify a novel role for TRAF1 as a modulator of oncogenic signals.

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Tan, X., Y. A. Alrashdan, H. Alkhouri, B. G. G. Oliver, C. L. Armour, and J. M. Hughes. "Airway smooth muscle CXCR3 ligand production: regulation by JAK-STAT1 and intracellular Ca2+." American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 11 (June 1, 2013): L790—L802. http://dx.doi.org/10.1152/ajplung.00356.2012.

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In asthma, airway smooth muscle (ASM) chemokine (C-X-C motif) receptor 3 (CXCR3) ligand production may attract mast cells or T lymphocytes to the ASM, where they can modulate ASM functions. In ASM cells (ASMCs) from people with or without asthma, we aimed to investigate JAK-STAT1, JNK, and Ca2+ involvement in chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11 production stimulated by interferon-γ, IL-1β, and TNF-α combined (cytomix). Confluent, growth-arrested ASMC were treated with inhibitors for pan-JAK (pyridone-6), JAK2 (AG-490), JNK (SP-600125), or the sarco(endo)plasmic reticulum Ca2+ATPase (SERCA) pump (thapsigargin), Ca2+ chelator (BAPTA-AM), or vehicle before and during cytomix stimulation for up to 24 h. Signaling protein activation as well as CXCL10/CXCL11 mRNA and protein production were examined using immunoblot analysis, real-time PCR, and ELISA, respectively. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to pyridone-6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion. Neither agent caused additional inhibition of release when used in combination with the JNK inhibitor SP-600125. Conversely, p65 NF-κB activation was higher in asthmatic than nonasthmatic ASMCs. BAPTA-AM abolished early CXCL10/CXCL11 mRNA production, whereas thapsigargin reduced it in asthmatic cells and inhibited CXCL10/CXCL11 release by both ASMC types. Despite these inhibitory effects, neither Ca2+ agent affected early activation of STAT1, JNK, or p65 NF-κB. In conclusion, intracellular Ca2+ regulated CXCL10/CXCL11 production but not early activation of the signaling molecules involved. In asthma, reduced ASM STAT1-JNK activation, increased NF-κB activation, and altered Ca2+ handling may contribute to rapid CXCR3 ligand production and enhanced inflammatory cell recruitment.

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18

Dhanasekaran, D. N., and E. P. Reddy. "JNK signaling in apoptosis." Oncogene 27, no. 48 (October 2008): 6245–51. http://dx.doi.org/10.1038/onc.2008.301.

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19

Leslie, M. "JNK-ing Cellular Poisons." Science of Aging Knowledge Environment 2003, no. 44 (November 5, 2003): 149nw—149. http://dx.doi.org/10.1126/sageke.2003.44.nw149.

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20

Davenport, R. J. "Feeling Spunky With JNK." Science of Aging Knowledge Environment 2005, no. 13 (March 30, 2005): nf24. http://dx.doi.org/10.1126/sageke.2005.13.nf24.

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21

Flight, Monica Hoyos. "Getting rid of JNK." Nature Reviews Drug Discovery 7, no. 12 (November 21, 2008): 975. http://dx.doi.org/10.1038/nrd2771.

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22

Heasley, Lynn E., and Sun-Young Han. "JNK Regulation of Oncogenesis." Molecules and Cells 21, no. 2 (April 2006): 167–73. http://dx.doi.org/10.1016/s1016-8478(23)12876-7.

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23

Chambers, Jeremy W., and Philip V. LoGrasso. "Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation." Journal of Biological Chemistry 286, no. 18 (March 16, 2011): 16052–62. http://dx.doi.org/10.1074/jbc.m111.223602.

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The JNK signaling cascade is critical for cellular responses to a variety of environmental and cellular stimuli. Although gene expression aspects of JNK signal transduction are well studied, there are minimal data on the physiological impact of JNK signaling. To bridge this gap, we investigated how JNK impacted physiology in HeLa cells. We observed that inhibition of JNK activity and JNK silencing with siRNA reduced the level of reactive oxygen species (ROS) generated during anisomycin-induced stress in HeLa cells. Silencing p38 had no significant impact on ROS generation under anisomycin stress. Moreover, JNK signaling mediated amplification of ROS production during stress. Mitochondrial superoxide production was shown to be the source of JNK-induced ROS amplification, as an NADPH oxidase inhibitor demonstrated little impact on JNK-mediated ROS generation. Using mitochondrial isolation from JNK null fibroblasts and targeting the mitochondrial scaffold of JNK, Sab, we demonstrated that mitochondrial JNK signaling was responsible for mitochondrial superoxide amplification. These results suggest that cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and amplify up to 80% of the ROS generated largely by Complex I. This work demonstrates that a sequence of events exist for JNK mitochondrial signaling whereby ROS activates JNK, thereby affecting mitochondrial physiology, which can have effects on cell survival and death.

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Bruna, A. "Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids." EMBO Journal 22, no. 22 (November 17, 2003): 6035–44. http://dx.doi.org/10.1093/emboj/cdg590.

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25

Stebbins, J. L., S. K. De, T. Machleidt, B. Becattini, J. Vazquez, C. Kuntzen, L. H. Chen, et al. "Identification of a new JNK inhibitor targeting the JNK-JIP interaction site." Proceedings of the National Academy of Sciences 105, no. 43 (October 15, 2008): 16809–13. http://dx.doi.org/10.1073/pnas.0805677105.

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26

Clarke, Penny, Suzanne M. Meintzer, Christian Widmann, Gary L. Johnson, and Kenneth L. Tyler. "Reovirus Infection Activates JNK and the JNK-Dependent Transcription Factor c-Jun." Journal of Virology 75, no. 23 (December 1, 2001): 11275–83. http://dx.doi.org/10.1128/jvi.75.23.11275-11283.2001.

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ABSTRACT Viral infection often perturbs host cell signaling pathways including those involving mitogen-activated protein kinases (MAPKs). We now show that reovirus infection results in the selective activation of c-Jun N-terminal kinase (JNK). Reovirus-induced JNK activation is associated with an increase in the phosphorylation of the JNK-dependent transcription factor c-Jun. Reovirus serotype 3 prototype strains Abney (T3A) and Dearing (T3D) induce significantly more JNK activation and c-Jun phosphorylation than does the serotype 1 prototypic strain Lang (T1L). T3D and T3A also induce more apoptosis in infected cells than T1L, and there was a significant correlation between the ability of these viruses to phosphorylate c-Jun and induce apoptosis. However, reovirus-induced apoptosis, but not reovirus-induced c-Jun phosphorylation, is inhibited by blocking TRAIL/receptor binding, suggesting that apoptosis and c-Jun phosphorylation involve parallel rather than identical pathways. Strain-specific differences in JNK activation are determined by the reovirus S1 and M2 gene segments, which encode viral outer capsid proteins (ς1 and μ1c) involved in receptor binding and host cell membrane penetration. These same gene segments also determine differences in the capacity of reovirus strains to induce apoptosis, and again a significant correlation between the capacity of T1L × T3D reassortant reoviruses to both activate JNK and phosphorylate c-Jun and to induce apoptosis was shown. The extracellular signal-related kinase (ERK) is also activated in a strain-specific manner following reovirus infection. Unlike JNK activation, ERK activation could not be mapped to specific reovirus gene segments, suggesting that ERK activation and JNK activation are triggered by different events during virus-host cell interaction.

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Thévenin, Anastasia F., Chati L. Zony, Brian J. Bahnson, and Roberta F. Colman. "GSTpi modulates JNK activity through a direct interaction with JNK substrate, ATF2." Protein Science 20, no. 5 (March 23, 2011): 834–48. http://dx.doi.org/10.1002/pro.609.

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Biggi, Silvia, Lucia Buccarello, Alessandra Sclip, Pellegrino Lippiello, Noemi Tonna, Cristiano Rumio, Daniele Di Marino, Maria Concetta Miniaci, and Tiziana Borsello. "Evidence of Presynaptic Localization and Function of the c-Jun N-Terminal Kinase." Neural Plasticity 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/6468356.

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The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form. By means of modelling design, we found that JNK, via the JBD domain, acts as a physiological effector on T-SNARE proteins; then using biochemical approaches we demonstrated the interaction between Syntaxin-1-JNK, Syntaxin-2-JNK, and Snap25-JNK. In addition, taking advance of the specific JNK inhibitor peptide, D-JNKI1, we defined JNK action on the SNARE complex formation. Finally, electrophysiological recordings confirmed the role of JNK in the presynaptic modulation of vesicle release. These data suggest that JNK-dependent phosphorylation of T-SNARE proteins may have an important functional role in synaptic plasticity.

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UDOMSINPRASERT, Rungrutai, Marie A. BOGOYEVITCH, and Albert J. KETTERMAN. "Reciprocal regulation of glutathione S-transferase spliceforms and the Drosophila c-Jun N-terminal kinase pathway components." Biochemical Journal 383, no. 3 (October 26, 2004): 483–90. http://dx.doi.org/10.1042/bj20040519.

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In mammalian systems, detoxification enzymes of the GST (glutathione S-transferase) family regulate JNK (c-Jun N-terminal kinase) signal transduction by interaction with JNK itself or other proteins upstream in the JNK pathway. In the present study, we have studied GSTs and their interaction with components of the JNK pathway from Diptera. We have evaluated the effects of four Delta class Anopheles dirus GSTs, GSTD1-1, GSTD2-2, GSTD3-3 and GSTD4-4, on the activity of full-length recombinant Drosophila HEP (mitogen-activated protein kinase kinase 7; where HEP stands for hemipterous) and the Drosophila JNK, as well as the reciprocal effect of these kinases on GST activity. Interestingly, even though these four GSTs are alternatively spliced products of the same gene and share >60% identity, they exerted different effects on JNK activity. GSTD1-1 inhibited JNK activity, whereas the other three GST isoforms activated JNK. GSTD2-2, GSTD3-3 and GSTD4-4 were inhibited 50–80% by HEP or JNK but GSTD1-1 was not inhibited by JNK. However, there were some similarities in the actions of HEP and JNK on these GSTs. For example, binding constants for HEP or JNK inhibiting a GST were similar (20–70 nM). Furthermore, after incubation of the GSTs with JNK, both JNK and the GSTs changed catalytic properties. The substrate specificities of both GSTs and JNK were also altered after their co-incubation. In addition, glutathione modulated the effects of JNK on GST activity. These results emphasize that different GST spliceforms possess different properties, both in their catalytic function and in their regulation of signalling through the JNK pathway.

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de los Reyes Corrales, Teresa, María Losada-Pérez, and Sergio Casas-Tintó. "JNK Pathway in CNS Pathologies." International Journal of Molecular Sciences 22, no. 8 (April 9, 2021): 3883. http://dx.doi.org/10.3390/ijms22083883.

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The c-Jun N-terminal kinase (JNK) signalling pathway is a conserved response to a wide range of internal and external cellular stress signals. Beside the stress response, the JNK pathway is involved in a series of vital regulatory mechanisms during development and adulthood that are critical to maintain tissue homeostasis. These mechanisms include the regulation of apoptosis, growth, proliferation, differentiation, migration and invasion. The JNK pathway has a diverse functionality and cell-tissue specificity, and has emerged as a key player in regeneration, tumorigenesis and other pathologies. The JNK pathway is highly active in the central nervous system (CNS), and plays a central role when cells need to cope with pathophysiological insults during development and adulthood. Here, we review the implications of the JNK pathway in pathologies of the CNS. More specifically, we discuss some newly identified examples and mechanisms of JNK-driven tumor progression in glioblastoma, regeneration/repair after an injury, neurodegeneration and neuronal cell death. All these new discoveries support the central role of JNK in CNS pathologies and reinforce the idea of JNK as potential target to reduce their detrimental effects.

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Meeker, Rick, and Alda Fernandes. "Osmotic and glutamate receptor regulation of c-Jun NH2-terminal protein kinase in neuroendocrine cells." American Journal of Physiology-Endocrinology and Metabolism 279, no. 3 (September 1, 2000): E475—E486. http://dx.doi.org/10.1152/ajpendo.2000.279.3.e475.

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Expression of a c-Jun NH2-terminal protein kinase (JNK), also known as stress-activated protein kinase (SAPK) in rodents, has been implicated in the ability of cells to respond to a variety of stressors. In nonmammalian cells, JNK participates in the regulation of cell volume in response to hyperosmotic stress. To explore the possibility that JNK may participate in the transduction of osmotic information in mammals, we evaluated the expression of JNK immunoreactivity in neuroendocrine cells of the supraoptic nucleus. Low basal expression of JNK-2 (SAPK-α) and JNK-3 (SAPK-β) was seen in vivo and in vitro. During water deprivation, JNK-2 increased in the supraoptic nucleus but not in the cortex. Osmotic or glutamate receptor stimulation in vitro also resulted in an increase in JNK-2 that was tetrodotoxin (TTX) insensitive and paralleled by increased nuclear phospho-c-Jun immunoreactivity. A TTX-sensitive increase in JNK-3 was seen in smaller neurons. Thus different JNK pathways may mediate individual cellular responses to osmotic stress, with JNK-2 linked to osmotic and glutamate receptor stimulation in magnocellular neuroendocrine cells.

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Kadoya, Takayuki, Ashwani Khurana, Marianna Tcherpakov, Kenneth D. Bromberg, Christine Didier, Limor Broday, Toshimasa Asahara, Anindita Bhoumik, and Ze'ev Ronai. "JAMP, a Jun N-Terminal Kinase 1 (JNK1)-Associated Membrane Protein, Regulates Duration of JNK Activity." Molecular and Cellular Biology 25, no. 19 (October 1, 2005): 8619–30. http://dx.doi.org/10.1128/mcb.25.19.8619-8630.2005.

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ABSTRACT We report the identification and characterization of JAMP (JNK1 [Jun N-terminal kinase 1]-associated membrane protein), a predicted seven-transmembrane protein that is localized primarily within the plasma membrane and associates with JNK1 through its C-terminal domain. JAMP association with JNK1 outcompetes JNK1 association with mitogen-activated protein kinase phosphatase 5, resulting in increased and prolonged JNK1 activity following stress. Elevated expression of JAMP following UV or tunicamycin treatment results in sustained JNK activity and a higher level of JNK-dependent apoptosis. Inhibition of JAMP expression by RNA interference reduces the degree and duration of JNK activation and concomitantly the level of stress-induced apoptosis. Through its regulation of JNK1 activity, JAMP emerges as a membrane-anchored regulator of the duration of JNK1 activity in response to diverse stress stimuli.

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Meriin, Anatoli B., Julia A. Yaglom, Vladimir L. Gabai, Dick D. Mosser, Leonard Zon, and Michael Y. Sherman. "Protein-Damaging Stresses Activate c-Jun N-Terminal Kinase via Inhibition of Its Dephosphorylation: a Novel Pathway Controlled by HSP72." Molecular and Cellular Biology 19, no. 4 (April 1, 1999): 2547–55. http://dx.doi.org/10.1128/mcb.19.4.2547.

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ABSTRACT Various stresses activate the c-Jun N-terminal kinase (JNK), which is involved in the regulation of many aspects of cellular physiology, including apoptosis. Here we demonstrate that in contrast to UV irradiation, heat shock causes little or no stimulation of the JNK-activating kinase SEK1, while knocking out the SEK1gene completely blocks heat-induced JNK activation. Therefore, we tested whether heat shock activates JNK via inhibition of JNK dephosphorylation. The rate of JNK dephosphorylation in unstimulated cells was high, and exposure to UV irradiation, osmotic shock, interleukin-1, or anisomycin did not affect this process. Conversely, exposure of cells to heat shock and other protein-damaging conditions, including ethanol, arsenite, and oxidative stress, strongly reduced the rate of JNK dephosphorylation. Under these conditions, we did not observe any effects on dephosphorylation of the homologous p38 kinase, suggesting that suppression of dephosphorylation is specific to JNK. Together, these data indicate that activation of JNK by protein-damaging treatments is mediated primarily by inhibition of a JNK phosphatase(s). Elevation of cellular levels of the major heat shock protein Hsp72 inhibited a repression of JNK dephosphorylation by these stressful treatments, which explains recent reports of the suppression of JNK activation by Hsp72.

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Morel, Caroline, Claire L. Standen, Dae Young Jung, Susan Gray, Helena Ong, Richard A. Flavell, Jason K. Kim, and Roger J. Davis. "Requirement of JIP1-Mediated c-Jun N-Terminal Kinase Activation for Obesity-Induced Insulin Resistance." Molecular and Cellular Biology 30, no. 19 (August 2, 2010): 4616–25. http://dx.doi.org/10.1128/mcb.00585-10.

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ABSTRACT The c-Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr103 replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat diet. The loss of JIP1-mediated JNK activation protected the mutant mice against obesity-induced insulin resistance. We conclude that JIP1-mediated JNK activation plays a critical role in metabolic stress regulation of the JNK signaling pathway.

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Lagadinou, Eleni D., Panos Ziros, Olga Tsopra, Eleni Thanopoulou, Alexandra Kouraklis, Marina Karakantza, and Nicholas C. Zoumbos. "C-JUN-NH2-Terminal Kinase Promotes Apoptosis, Suppresses P-Glycoprotein Mediated Multidrug Resistance but Enhances MRP Mediated Efflux in AML Cells." Blood 108, no. 11 (November 16, 2006): 4379. http://dx.doi.org/10.1182/blood.v108.11.4379.4379.

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Abstract JNK has been implicated in distinct cellular events, as proliferation, cellular transformation and apoptosis. JNK has also been recently reported to reverse MDR1 mediated drug resistance and increase sensitivity to chemotherapeutic agents in non-hematopoietic cancer cells. As acquired drug resistance represents a major obstacle in successful therapy of Acute Myeloid Leukemia (AML), the significance of JNK activation in relation to apoptosis induction and drug resistance in AML was sought. JNK is active in U937 leukemia cells and undergoes further activation upon treatment with therapeutically relevant concentrations of daunomycin. Daunomycin induces massive apoptosis in these cells, which is significantly reduced if U937 cells are preincubated with JNK inhibitor 420116. MDR1 and MRP expression levels are low in U937 cells. URD cells, a U937 deritive cell line characterized by resistance to adriamycin, was tested. Interestingly, no basal JNK activity was detected in URD cells and daunomycin treatment did not activate JNK nor induced apoptosis, albeit abundant JNK protein expression. JNK has been proposed to be prerequisite for mediating drug resistance in HL60 cells, by up regulating GSTP1 and MRP efflux pump. GSTP1 was strongly expressed in URD cells in the absence of JNK activation, but MRP expression was insignificant. Moreover, GSTP1 contributed to JNK inactivation in these cells, as immunoprecipitation experiments revealed a complex of GSTP1 with JNK. MDR1 activity in URD cells was 90%, as detected by the calcein AM efflux assay. Transfection of URD cells with SEKED plasmid expressing JNK decreased MDR1 activity by 35% while MRP activity exhibited >3 fold increase, from 5% to 18,4%. 29% of URD cells underwent apoptosis after 24hr of treatment with 1μM daunomycin compared to 5% of cells transfected with empty vector, as measured by annexin V/ PI and DAPI staining. To validate our results to primary AML cells, 25 AML bone marrow samples were tested for JNK activation, apoptosis induction after daunomycin treatment and GSTP1, MDR1 and MRP expresion levels. Basal JNK activity was detected in 58% of patients and did not correlate with apoptosis susceptibility or MDR1 and MRP expression levels. JNK activation within 1 hr of treatment occurred in 9 samples (36%) and strongly correlated with statistically significant apoptosis (p=0,0044< 0,05) after 12hr of continuous drug exposure. In 16 samples (64%), JNK activation was not observed upon daunomycin treatment and apoptosis did not reach a statistically significant level (p=0,3>0,05). Chemotherapy induced JNK activation was irrelevant to basal JNK activity status. GSTP1 was strongly expressed in all samples examined. Our experimental data indicate that JNK activation is implicated in distinct cellular processes in response to chemotherapy. Activation of JNK correlated with apoptosis induction in U937 cells and in primary leukemia samples. Moreover, JNK activity was lost in resistant URD cells, perhaps due to GSTP1 inhibition, and when expressed induced MDR1 downregulation and apoptosis. The proapoptotic function of JNK in URD cells can not be attributed only to MDR1 downregulation, since it is also observed in U937 cells, characterized by low MDR1 activity. Interestingly, JNK expression in URD cells also upregulated the MRP efflux pump. Further studies are needed to elucidate whether JNK represents a possible drug target to overcome drug resistance in AML.

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Stricker, Stephen A., and Niharika Ravichandran. "The potential roles of c-Jun N-terminal kinase (JNK) during the maturation and aging of oocytes produced by a marine protostome worm." Zygote 25, no. 6 (October 16, 2017): 686–96. http://dx.doi.org/10.1017/s0967199417000533.

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SummaryPrevious investigations have indicated that c-Jun N-terminal kinase (JNK) regulates the maturation and aging of oocytes produced by deuterostome animals. In order to assess the roles of this kinase in a protostome, oocytes of the marine nemertean worm Cerebratulus were stimulated to mature and subsequently aged before being probed with phospho-specific antibodies against active forms of JNK and maturation-promoting factor (MPF). Based on blots of maturing oocytes, a 40-kD putative JNK is normally activated during germinal vesicle breakdown (GVBD), which begins at 30 min post-stimulation with seawater, whereas treating immature oocytes with JNK inhibitors downregulates both the 40-kD JNK signal and GVBD, collectively suggesting a 40-kD JNK may facilitate oocyte maturation. Along with this JNK activity, mature oocytes also exhibit high levels of MPF at 2 h post-stimulation. However, by ~6–8 h post-GVBD, mature oocytes lose the 40-kD JNK signal, and at ~20–30 h of aging, an ~48-kD phospho-JNK band arises as oocytes deactivate MPF and begin to lyse during a necroptotic-like mode of death. Accordingly, JNK inhibitors reduce the aging-related 48-kD JNK phosphorylation while maintaining MPF activity and retarding oocyte degradation. Such findings suggest that a 48-kD JNK may help deactivate MPF and trigger death. Possible mechanisms by which JNK activation either together with, or independently of, protein neosynthesis might stimulate oocyte degradation are discussed.

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Wei, Lin, Yinglin Liu, Hideaki Kaneto, and Barry L. Fanburg. "JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 298, no. 6 (June 2010): L863—L869. http://dx.doi.org/10.1152/ajplung.00281.2009.

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JNK is a member of the MAPK family and has essential roles in inflammation and cell differentiation and apoptosis. In recent years, there have been accumulating data indicating a novel role for JNK in cell growth and migration. In this report, we demonstrate that JNK activity is necessary for serotonin (5-HT)-induced proliferation and migration of bovine pulmonary artery smooth muscle cells (PASMCs). Stimulation with 5-HT was found to lead to activation of JNK with a maximal activation at 10 min. Inhibition of JNK with its specific inhibitor, SP-600125, or its dominant-negative form, DN-JNK, significantly reduced 5-HT-stimulated [3H]thymidine incorporation and cyclin D1 expression. A similar inhibitory effect on SMC migration produced by 5-HT, as detected by a wound healing assay, was observed with inhibition of JNK. Furthermore, inhibition of 5-HT receptors 1B and 2A, but not inhibition of the 5-HT transporter, blocked 5-HT-induced JNK activation. Inhibition of phosphatidylinositol 3-kinase (PI3K) with LY-294002 and wortmannin had little or no effect on 5-HT-induced JNK phosphorylation, but JNK inhibitor SP-600125 and DN-JNK blocked 5-HT-stimulated phosphorylation of Akt and its downstream effectors, p70S6K1 and S6, indicating that Akt is a downstream effector of JNK. Activation of Akt by 5-HT was blocked only minimally, if at all, by inhibitors of ERK and p38 MAPK, indicating a uniqueness of JNK MAPK in this activation of Akt. Coimmunoprecipitation showed binding of Akt to JNK, further supporting the interaction of JNK and Akt. Thus JNK is a critical molecule in 5-HT-induced PASMC proliferation and migration and may act at an important point for cross talk of the MAPK and PI3K pathways. Its activation by 5-HT is initiated through 5-HT 1B and 2A receptors, and its stimulation of SMC proliferation and migration occurs through the Akt pathway.

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Xu, Bing, Yaling Zhou, Karmin O, Patrick C. Choy, Grant N. Pierce, and Yaw L. Siow. "Regulation of stress-associated scaffold proteins JIP1 and JIP3 on the c-Jun NH2-terminal kinase in ischemia–reperfusion." Canadian Journal of Physiology and Pharmacology 88, no. 11 (November 2010): 1084–92. http://dx.doi.org/10.1139/y10-088.

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Ischemia–reperfusion (IR)-induced cell apoptosis involves the activation of c-Jun NH2-terminal kinase (JNK). The activation of JNK requires the presence of scaffold proteins called JNK-interacting proteins (JIP), which bind several members of a signaling cascade for proper signaling specificity. In this study, the expression of scaffold proteins JIP1 and JIP3 and their roles in the regulation of JNK activity were investigated in simulated IR in a cell model (H9c2). JIP1 protein expression was significantly decreased, whereas JIP3 protein expression was increased in IR H9c2 cells. Adenovirus-induced overexpression of JIP1 reduced IR-induced JNK activity and apoptosis. Conversely, overexpression of JIP3 increased JNK activity and apoptosis following IR. Depletion of endogenous JIP1 by siRNA treatment increased the IR-induced JNK activity, whereas siRNA-mediated depletion of endogenous JIP3 inhibited JNK activity. These results suggest that JIP1 and JIP3 play important roles in the activation of JNK during simulated IR challenge in H9c2 cells.

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Chu, Shijian, and Thomas J. Ferro. "Identification of a hydrogen peroxide-induced PP1-JNK1-Sp1 signaling pathway for gene regulation." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 5 (November 2006): L983—L992. http://dx.doi.org/10.1152/ajplung.00454.2005.

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Oxidative stress often results in changes in gene expression through the regulation of transcription factors. In this study, we examine how Sp1 phosphorylation is regulated by H2O2 in a human alveolar epithelial cell line (HAE). Treatment of HAE cells with H2O2 increases phosphorylation of Sp1 and activates JNK. To establish a relationship between JNK and Sp1, we show that JNK activator anisomycin increases Sp1 phosphorylation, and JNK inhibitors as well as dominant-negative JNK1 attenuate H2O2-induced Sp1 phosphorylation. Additionally, JNK1 directly phosphorylates Sp1 in vitro, reducing Sp1 binding to DNA. These results demonstrate the role of JNK in H2O2-induced Sp1 phosphorylation. Because H2O2 inhibits Ser/Thr protein phosphatase-1 (PP1), we examined the role of PP1 in the regulation of JNK. Similar to H2O2, inhibition of PP1 induces phosphorylation of Sp1 and activation of JNK in HAE cells. Inhibition of JNK activity using either inhibitors or dominant-negative mutant JNK1 suppresses PP1 inhibition-induced Sp1 phosphorylation. Furthermore, PP1 directly inactivates JNK1 in vitro. These data suggest that 1) H2O2 increases the phosphorylation level of Sp1, 2) Sp1 is a target of the JNK pathway, 3) PP1 regulates JNK activation, and 4) the “PP1-JNK” pathway plays a role in H2O2-induced Sp1 phosphorylation in lung epithelial cells.

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Zapata, Heidi J., Masako Nakatsugawa, and Jennifer F. Moffat. "Varicella-Zoster Virus Infection of Human Fibroblast Cells Activates the c-Jun N-Terminal Kinase Pathway." Journal of Virology 81, no. 2 (November 1, 2006): 977–90. http://dx.doi.org/10.1128/jvi.01470-06.

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ABSTRACT The transcription factors ATF-2 and c-Jun are important for transactivation of varicella-zoster virus (VZV) genes. c-Jun is activated by the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase pathway that responds to stress and cytokines. To study the effects of VZV on this pathway, confluent human foreskin fibroblasts were infected with cell-associated VZV for 1 to 4 days. Immunoblots showed that phosphorylated JNK and c-Jun levels increased in VZV-infected cells, and kinase assays determined that phospho-JNK was active. Phospho-JNK was detected after 24 h, and levels rose steadily over 4 days in parallel with accumulation of VZV antigen. The two main activators of JNK are MKK4 and MKK7, and levels of their active, phosphorylated forms also increased. The competitive inhibitor of JNK, SP600125, caused a dose-dependent reduction in VZV yield (50% effective concentration, ≅8 μM). Specificity was verified by immunoblotting; phospho-c-Jun was eliminated by 18 μM SP600125 in VZV-infected cells. Immunofluorescent confocal microscopy showed that phospho-c-Jun and most of phospho-JNK were in the nuclei of VZV-infected cells; some phospho-JNK was in the cytoplasm. MKK4, MKK7, JNK, and phospho-JNK were detected by immunoblotting in purified preparations of VZV virions, but c-Jun was absent. JNK was located in the virion tegument, as determined by biochemical fractionation and immunogold transmission electron microscopy. Overall, these results demonstrate the importance of the JNK pathway for VZV replication and advance the idea that JNK is a useful drug target against VZV.

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Fujii, Nobuharu, Marni D. Boppart, Scott D. Dufresne, Patricia F. Crowley, Alison C. Jozsi, Kei Sakamoto, Haiyan Yu, et al. "Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity." American Journal of Physiology-Cell Physiology 287, no. 1 (July 2004): C200—C208. http://dx.doi.org/10.1152/ajpcell.00415.2003.

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c-Jun NH2-terminal kinase (JNK) is highly expressed in skeletal muscle and is robustly activated in response to muscle contraction. Little is known about the biological functions of JNK signaling in terminally differentiated muscle cells, although this protein has been proposed to regulate insulin-stimulated glycogen synthase activity in mouse skeletal muscle. To determine whether JNK signaling regulates contraction-stimulated glycogen synthase activation, we applied an electroporation technique to induce JNK overexpression (O/E) in mouse skeletal muscle. Ten days after electroporation, in situ muscle contraction increased JNK activity 2.6-fold in control muscles and 15-fold in the JNK O/E muscles. Despite the enormous activation of JNK activity in JNK O/E muscles, contraction resulted in similar increases in glycogen synthase activity in control and JNK O/E muscles. Consistent with these findings, basal and contraction-induced glycogen synthase activity was normal in muscles of both JNK1- and JNK2-deficient mice. JNK overexpression in muscle resulted in significant alterations in the basal phosphorylation state of several signaling proteins, such as extracellular signal-regulated kinase 1/2, p90 S6 kinase, glycogen synthase kinase 3, protein kinase B/Akt, and p70 S6 kinase, in the absence of changes in the expression of these proteins. These data suggest that JNK signaling regulates the phosphorylation state of several kinases in skeletal muscle. JNK activation is unlikely to be the major mechanism by which contractile activity increases glycogen synthase activity in skeletal muscle.

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Wagner, Andreas C. C., Luca Mazzucchelli, Matthew Miller, Anna Marie Camoratto, and Burkhard Göke. "CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates caerulein pancreatitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 278, no. 1 (January 1, 2000): G165—G172. http://dx.doi.org/10.1152/ajpgi.2000.278.1.g165.

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Pancreatic caerulein-induced activation of c-Jun NH2-terminal kinase (JNK) has been reported, and JNK has been proposed as a mediator during induction of hyperstimulated pancreatitis. CEP-1347 has recently been described as a specific JNK inhibitor. We tested whether CEP-1347 inhibits caerulein-induced pancreatic JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited acinar caerulein-induced JNK activation with nearly complete inhibition at 2 μM but had no effect on digestive enzyme release. For in vivo studies, rats were pretreated with CEP-1347 before caerulein hyperstimulation. For assessment of JNK activation and histological alterations, animals were killed 30 min or 2 and 4 h after caerulein hyperstimulation, respectively. Pancreatic wet weight, serum enzyme levels, and pancreatic activity of p38 and extracellular signal-regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly activated JNK, p38, and ERK. CEP-1347 pretreatment dose dependently reduced caerulein-induced pancreatic JNK activation without p38 or ERK inhibition. JNK inhibition also reduced pancreatic edema formation and reduced histological severity of pancreatitis. Thus we show that CEP-1347 inhibits JNK activation in vivo and ameliorates caerulein-induced pancreatitis.

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Sun, Kai-Hui, Hyoung-gon Lee, Mark A. Smith, and Kavita Shah. "Direct and Indirect Roles of Cyclin-dependent Kinase 5 as an Upstream Regulator in the c-Jun NH2-Terminal Kinase Cascade: Relevance to Neurotoxic Insults in Alzheimer's Disease." Molecular Biology of the Cell 20, no. 21 (November 2009): 4611–19. http://dx.doi.org/10.1091/mbc.e09-05-0433.

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Significant increase in JNK, c-Jun, and Cdk5 activities are reported in Alzheimer's disease (AD). Inhibition of c-Jun prevents neuronal cell death in in vivo AD models, highlighting it as a major JNK effector. Both JNK and Cdk5 promote neurodegeneration upon deregulation; however, Cdk5 has not been mechanistically linked to JNK or c-Jun. This study presents the first mechanism showing Cdk5 as a major regulator of the JNK cascade. Deregulated Cdk5 induces biphasic activation of JNK pathway. The first phase revealed c-Jun as a direct substrate of Cdk5, whose activation is independent of reactive oxygen species (ROS) and JNK. In the second phase, Cdk5 activates c-Jun via ROS-mediated activation of JNK. Rapid c-Jun activation is supported by in vivo data showing c-Jun phosphorylation in cerebral cortex upon p25 induction in transgenic mice. Cdk5-mediated biphasic activation of c-Jun highlights c-Jun, rather than JNK, as an important therapeutic target, which was confirmed in neuronal cells. Finally, Cdk5 inhibition endows superior protection against neurotoxicity, suggesting that Cdk5 is a preferable therapeutic target for AD relative to JNK and c-Jun.

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Manieri, Elisa, Cintia Folgueira, María Elena Rodríguez, Luis Leiva-Vega, Laura Esteban-Lafuente, Chaobo Chen, Francisco Javier Cubero, et al. "JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16492–99. http://dx.doi.org/10.1073/pnas.2002672117.

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Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.

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Gao, Yanqin, Armando P. Signore, Wei Yin, Guodong Cao, Xiao-Ming Yin, Fengyan Sun, Yumin Luo, Steven H. Graham, and Jun Chen. "Neuroprotection against Focal Ischemic Brain Injury by Inhibition of c-Jun N-Terminal Kinase and Attenuation of the Mitochondrial Apoptosis-Signaling Pathway." Journal of Cerebral Blood Flow & Metabolism 25, no. 6 (February 16, 2005): 694–712. http://dx.doi.org/10.1038/sj.jcbfm.9600062.

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c-Jun N-terminal kinase (JNK) is an important stress-responsive kinase that is activated by various forms of brain insults. In this study, we have examined the role of JNK activation in neuronal cell death in a murine model of focal ischemia and reperfusion; furthermore, we investigated the mechanism of JNK in apoptosis signaling, focusing on the mitochondrial-signaling pathway. We show here that JNK activity was induced in the brain 0.5 to 24 h after ischemia. Systemic administration of SP600125, a small molecule JNK-specific inhibitor, diminished JNK activity after ischemia and dose-dependently reduced infarct volume. c-Jun N-terminal kinase inhibition also attenuated ischemia-induced expression of Bim, Hrk/DP5, and Fas, but not the expression of Bcl-2 or FasL. In strong support of a role for JNK in promoting the mitochondrial apoptosis-signaling pathway, JNK inhibition prevented ischemia-induced mitochondrial translocation of Bax and Bim, release of cytochrome c and Smac, and activation of caspase-9 and caspase-3. The potential mechanism by which JNK promoted Bax translocation after ischemia was further studied using coimmunoprecipitation, and the results revealed that JNK activation caused serine phosphorylation of 14-3-3, a cytoplasmic sequestration protein of Bax, leading to Bax disassociation from 14-3-3 and subsequent translocation to mitochondria. These results confirm the role of JNK as a critical cell death mediator in ischemic brain injury, and suggest that one of the mechanisms by which JNK triggers the mitochondrial apoptosis-signaling pathway is via promoting Bax and Bim translocation.

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Saunders, Philip O., Kenneth F. Bradstock, and Linda J. Bendall. "The JNK Pathway Is a Significant Determinant of Sensitivity to DNA Damaging Agents in Pre-B ALL." Blood 114, no. 22 (November 20, 2009): 3786. http://dx.doi.org/10.1182/blood.v114.22.3786.3786.

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Abstract Abstract 3786 Poster Board III-722 The JNK pathway is reported to facilitate AP1 binding and promote apoptosis depending on cell type and environmental conditions. We have previously reported RAD001 (16μM) induces JNK pathway activation in pre-B ALL cells. We sought to evaluate the impact of changes in JNK pathway activation on pre-B ALL viability in vitro. Using JNK inhibitor SP600125 titrated to inhibit c-Jun activation, we determined that cell death in pre-B ALL cells treated with RAD001 (16μM) alone was not JNK dependent. In contrast, combining RAD001 (16μM) with DNA damaging agents significantly enhanced JNK dependent death. This difference indicates that additional factors, including genotoxic stress, are required for JNK activation to induce pre-B ALL cell death. The JNK pathway is reported to suppress transcriptional activation of key mediators of the DNA damage response. We observed that JNK activation in cells treated with RAD001 (16μM) and DNA damaging agents was associated with suppression of p53 and p21 relative to DNA damage alone. This result was supported by the observation of enhanced p53 and p21 expression in pre-B ALL cells treated with DNA damaging agents in the presence of the JNK inhibitor SP600125. Analysis of DNA content and proliferation antigen expression in pre-B ALL cells treated with RAD001 (16μM) and DNA damaging agents revealed JNK activation was associated with a significant increase in the proportion of cells in S phase, relative to DNA damage alone, which caused a G1 and G2 cell cycle arrest. Further evidence that the JNK pathway impacts on the DNA damage response was provided by the observation that pre-B ALL cells treated with DNA damaging agents and JNK inhibitor SP600125 demonstrated reduced PCNA expression at G1 and G2 and reduced expression of mitotic antigen phospho-Histone–H3. This is consistent with enhanced regulation at G1-S and G2-M checkpoints. The results indicate changes in JNK pathway activation impact on the cell cycle response to DNA damage. In conclusion we have identified that the JNK pathway has a significant impact on the sensitivity of pre-B ALL cells to DNA damaging agents. JNK activation in the presence of genotoxic stress significantly enhanced pre-B ALL cell death, associated with suppression of key mediators of the DNA damage response, p53 and p21. We found that changes in JNK activation altered the cell cycle response to DNA damage. Further study is required to determine if changes in cell cycle regulation in the presence of DNA damage is causal to JNK dependent cell death. Additional studies to identify intracellular signal pathways which facilitate JNK dependent cell death are warranted. Our observations suggest combining agents which induce JNK activation with conventional chemotherapy or selected novel agents has the potential to enhance clinical responses in pre-B ALL. Disclosures: No relevant conflicts of interest to declare.

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Sengupta Ghosh, Arundhati, Bei Wang, Christine D. Pozniak, Mark Chen, Ryan J. Watts, and Joseph W. Lewcock. "DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity." Journal of Cell Biology 194, no. 5 (September 5, 2011): 751–64. http://dx.doi.org/10.1083/jcb.201103153.

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The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.

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Tang, Christine, Lucy Shu Nga Yeung, Khajag Koulajian, Liling Zhang, Kevin Tai, Allen Volchuk, and Adria Giacca. "Glucose-Induced β-Cell Dysfunction In Vivo: Evidence for a Causal Role of C-jun N-terminal Kinase Pathway." Endocrinology 159, no. 11 (September 11, 2018): 3643–54. http://dx.doi.org/10.1210/en.2018-00566.

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Abstract Prolonged elevation of glucose can adversely affect β-cell function. Oxidative stress, which has been implicated in glucose-induced β-cell dysfunction, can activate c-jun N-terminal kinase (JNK). However, whether JNK is causal in glucose-induced β-cell dysfunction in vivo is unclear. Therefore, we aimed at investigating the causal role of JNK activation in in vivo models of glucose-induced β-cell dysfunction. Glucose-induced β-cell dysfunction was investigated in the presence or absence of JNK inhibition. JNK inhibition was achieved using either (i) the JNK-specific inhibitor SP600125 or (ii) JNK-1–null mice. (i) Rats or mice were infused intravenously with saline or glucose with or without SP600125. (ii) JNK-1 null mice and their littermate wild-type controls were infused intravenously with saline or glucose. Following the glucose infusion periods in rats and mice, β-cell function was assessed in isolated islets or in vivo using hyperglycemic clamps. Forty-eight-hour hyperglycemia at ~20 mM in rats or 96-hour hyperglycemia at ~13 mM in mice impaired β-cell function in isolated islets and in vivo. Inhibition of JNK using either SP600125 or JNK-1–null mice prevented glucose-induced β-cell dysfunction in isolated islets and in vivo. Islets of JNK-1–null mice exposed to hyperglycemia in vivo showed an increase in Pdx-1 and insulin 2 mRNA, whereas islets of wild-type mice did not. Together, these data show that JNK pathway is involved in glucose-induced β-cell dysfunction in vivo and is thus a potential therapeutic target for type 2 diabetes.

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Weiss, Linda, Alan J. Whitmarsh, Derek D. Yang, Mercedes Rincón, Roger J. Davis, and Richard A. Flavell. "Regulation of c-Jun NH2-terminal Kinase ( Jnk) Gene Expression during T Cell Activation." Journal of Experimental Medicine 191, no. 1 (January 3, 2000): 139–46. http://dx.doi.org/10.1084/jem.191.1.139.

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The c-Jun NH2-terminal kinases (JNKs) are a group of mitogen-activated protein (MAP) kinases that participate in signal transduction events mediating specific cellular functions. Activation of JNK is regulated by phosphorylation in response to cellular stress and inflammatory cytokines. Here, we demonstrate that JNK is regulated by a second, novel mechanism. Induction of Jnk gene expression is required in specific tissues before activation of this signaling pathway. The in vivo and in vitro ligation of the T cell receptor (TCR) leads to induction of JNK gene and protein expression. TCR signals are sufficient to induce JNK expression, whereas JNK phosphorylation also requires CD28-mediated costimulatory signals. Therefore, both expression and activation contribute to the regulation of the JNK pathway to ensure proper control during the course of an immune response.

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WILTSHIRE, Carolyn, Masato MATSUSHITA, Satoshi TSUKADA, David A. F. GILLESPIE, and Gerhard H. W. MAY. "A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5), associates with mitochondria." Biochemical Journal 367, no. 3 (November 1, 2002): 577–85. http://dx.doi.org/10.1042/bj20020553.

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We have identified a novel c-Jun N-terminal kinase (JNK)-interacting protein, Sab, by yeast two-hybrid screening. Sab binds to and serves as a substrate for JNK in vitro, and was previously found to interact with the Src homology 3 (SH3) domain of Bruton's tyrosine kinase (Btk). Inspection of the sequence of Sab reveals the presence of two putative mitogen-activated protein kinase interaction motifs (KIMs) similar to that found in the JNK docking domain of the c-Jun transcription factor, and four potential serine—proline JNK phosphorylation sites in the C-terminal half of the molecule. Using deletion and site-directed mutagenesis, we demonstrate that the most N-terminal KIM in Sab is essential for JNK binding, and that, as with c-Jun, physical interaction with JNK is necessary for Sab phosphorylation. Interestingly, confocal immunocytochemistry and cell fractionation studies indicate that Sab is associated with mitochondria, where it co-localizes with a fraction of active JNK. These and previously reported properties of Sab suggest a possible role in targeting JNK to this subcellular compartment and/or mediating cross-talk between the Btk and JNK signal transduction pathways.

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Journal articles on the topic 'JNK'

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