Journal articles: 'C-Jun N-terminal kinase (JNK)'

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Liu, Jing, Yuzuru Minemoto, and Anning Lin. "c-Jun N-Terminal Protein Kinase 1 (JNK1), but Not JNK2, Is Essential for Tumor Necrosis Factor Alpha-Induced c-Jun Kinase Activation and Apoptosis." Molecular and Cellular Biology 24, no. 24 (December 15, 2004): 10844–56. http://dx.doi.org/10.1128/mcb.24.24.10844-10856.2004.

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ABSTRACT Two ubiquitously expressed isoforms of c-Jun N-terminal protein kinase (JNK), JNK1 and JNK2, have shared functions and different functions. However, the molecular mechanism is unknown. Here we report that JNK1, but not JNK2, is essential for tumor necrosis factor alpha (TNF-α)-induced c-Jun kinase activation, c-Jun expression, and apoptosis. Using mouse fibroblasts deficient in either Jnk1 or Jnk2, we found that JNK1 was activated by TNF-α, whereas JNK2 activation was negligible. In addition, JNK2 interfered with JNK1 activation via its “futile” phosphorylation by upstream kinases. Consequently, expression and activation of c-Jun, which depends on JNK activity, were impaired in Jnk1 null cells but enhanced in Jnk2 null cells. TNF-α-induced apoptosis was also suppressed in Jnk1 null fibroblasts but increased in Jnk2 null cells. Thus, our results provide a molecular mechanism underlying the different biological functions of JNK isoforms.

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Ngoei, Kevin R. W., Bruno Catimel, Nicole Church, Daisy S. Lio, Con Dogovski, Matthew A. Perugini, Paul M. Watt, Heung-Chin Cheng, Dominic C. H. Ng, and Marie A. Bogoyevitch. "Characterization of a novel JNK (c-Jun N-terminal kinase) inhibitory peptide." Biochemical Journal 434, no. 3 (February 24, 2011): 399–413. http://dx.doi.org/10.1042/bj20101244.

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An improved understanding of the roles of protein kinases in intracellular signalling and disease progression has driven significant advances in protein kinase inhibitor discovery. Peptide inhibitors that target the kinase protein substrate-binding site have continued to attract attention. In the present paper, we describe a novel JNK (c-Jun N-terminal kinase) inhibitory peptide PYC71N, which inhibits JNK activity in vitro towards a range of recombinant protein substrates including the transcription factors c-Jun, ATF2 (activating trancription factor 2) and Elk1, and the microtubule regulatory protein DCX (doublecortin). Analysis of cell culture studies confirmed the actions of a cell-permeable version of PYC71 to inhibit c-Jun phosphorylation during acute hyperosmotic stress. The analysis of the in vitro data for the kinetics of this inhibition indicated a substrate–inhibitor complex-mediated inhibition of JNK by PYC71N. Alanine-scanning replacement studies revealed the importance of two residues (PYC71N Phe9 or Phe11 within an FXF motif) for JNK inhibition. The importance of these residues was confirmed through interaction studies showing that each change decreased interaction of the peptide with c-Jun. Furthermore, PYC71N interacted with both non-phosphorylated (inactive) JNK1 and the substrate c-Jun, but did not recognize active JNK1. In contrast, a previously characterized JNK-inhibitory peptide TIJIP [truncated inhibitory region of JIP (JNK-interacting protein)], showed stronger interaction with active JNK1. Competition binding analysis confirmed that PYC71N inhibited the interaction of c-Jun with JNK1. Taken together, the results of the present study define novel properties of the PYC71N peptide as well as differences from the characterized TIJIP, and highlight the value of these peptides to probe the biochemistry of JNK-mediated substrate interactions and phosphorylation.

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Messoussi, A., G. Chevé, K. Bougrin, and A. Yasri. "Insight into the selective inhibition of JNK family members through structure-based drug design." MedChemComm 7, no. 4 (2016): 686–92. http://dx.doi.org/10.1039/c5md00562k.

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The c-Jun N-terminal kinase (JNK) family, which comprises JNK1, JNK2 and JNK3, belongs to the mitogen-activated protein kinase (MAPK) superfamily, whose members regulate myriad biological processes, including those implicated in tumorigenesis and neurodegenerative disorders.

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Schepetkin, Igor A., Oleksander S. Karpenko, Anastasia R. Kovrizhina, Liliya N. Kirpotina, Andrei I. Khlebnikov, Stepan I. Chekal, Alevtyna V. Radudik, Maryna O. Shybinska, and Mark T. Quinn. "Novel Tryptanthrin Derivatives with Selectivity as c–Jun N–Terminal Kinase (JNK) 3 Inhibitors." Molecules 28, no. 12 (June 16, 2023): 4806. http://dx.doi.org/10.3390/molecules28124806.

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The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation, cell survival, and inflammation. Because of emerging data suggesting that JNK3 may play an important role in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease, as well as cancer pathogenesis, we sought to identify JNK inhibitors with increased selectivity for JNK3. A panel of 26 novel tryptanthrin-6-oxime analogs was synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses. Compounds 4d (8-methoxyindolo[2,1-b]quinazolin-6,12-dione oxime) and 4e (8-phenylindolo[2,1-b]quinazolin-6,12-dione oxime) had high selectivity for JNK3 versus JNK1 and JNK2 and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue cells and interleukin-6 (IL-6) production by MonoMac-6 monocytic cells in the low micromolar range. Likewise, compounds 4d, 4e, and pan-JNK inhibitor 4h (9-methylindolo[2,1-b]quinazolin-6,12-dione oxime) decreased LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of these compounds in the JNK3 catalytic site that were in agreement with the experimental data on JNK3 binding. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems with selectivity for JNK3.

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Sedmíková, M., J. Petr, A. Dörflerová, J. Nevoral, B. Novotná, T. Krejčová, E. Chmelíková, and L. Tůmová. "Inhibition of c-Jun N-terminal kinase (JNK) suppresses porcine oocyte ageing in vitro." Czech Journal of Animal Science 58, No. 12 (November 25, 2013): 535–45. http://dx.doi.org/10.17221/7088-cjas.

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Oocyte ageing is a complex of processes that occur when matured in vitro oocytes are, after reaching the metaphase II stage, exposed to further in vitro culture. Aged oocytes remaining at the metaphase II stage undergo spontaneous parthenogenetic activation, or cellular death, through apoptosis (fragmentation) or lysis. The key factor in apoptotic pathway regulation is c-Jun-N-terminal kinase (JNK), stress kinase from the mitogene-activated protein kinase (MAPK) family. To investigate the effect of JNK inhibition on porcine oocytes ageing, cleavage rate, and embryonic development after parthenogenetic activation, DNA fragmentation, and pro-apoptotic factor Bax expression, we cultured in vitro matured oocytes for another 1–4 days in the presence of a JNK inhibitor. The inhibition of JNK significantly protected the oocytes from fragmentation (0% of fragmented oocytes under JNK inhibition vs. 13.4% of fragmented oocytes in the control group, 2nd day of ageing) and increased the percentage of parthenogenetically activated oocytes (82 vs 57.7%, 2nd day of ageing). The embryonic development of oocytes parthenogenetically activated after 24 h of ageing was influenced by JNK inhibition as well. The percentage of oocytes at the morula stage, after seven days of cultivation, was significantly increased when oocytes aged in the presence of a JNK inhibitor (42.5%) by comparison to the percentage of oocytes exposed to ageing in an inhibitor-free medium (23.3%). DNA fragmentation was significantly suppressed by JNK inhibition from the 1st day of ageing, but the expression of pro-apoptotic factor Bax in the oocytes was not influenced. On the basis of our experiments, we can conclude that JNK inhibition suppresses apoptosis and DNA fragmentation of aged oocytes and improves their embryonic development following the parthenogenetic activation. However, to completely eliminate all ageing related processes is insufficient.

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Unger, Elizabeth K., Merisa L. Piper, Louise E. Olofsson, and Allison W. Xu. "Functional Role of c-Jun-N-Terminal Kinase in Feeding Regulation." Endocrinology 151, no. 2 (February 1, 2010): 671–82. http://dx.doi.org/10.1210/en.2009-0711.

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c-Jun-N-terminal kinase (JNK) is a signaling molecule that is activated by proinflammatory signals, endoplasmic reticulum (ER) stress, and other environmental stressors. Although JNK has diverse effects on immunological responses and insulin resistance in peripheral tissues, a functional role for JNK in feeding regulation has not been established. In this study, we show that central inhibition of JNK activity potentiates the stimulatory effects of glucocorticoids on food intake and that this effect is abolished in mice whose agouti-related peptide (AgRP) neurons are degenerated. JNK1-deficient mice feed more upon central administration of glucocorticoids, and glucocorticoid receptor nuclear immunoreactivity is enhanced in the AgRP neurons. JNK inhibition in hypothalamic explants stimulates Agrp expression, and JNK1-deficient mice exhibit increased Agrp expression, heightened hyperphagia, and weight gain during refeeding. Our study shows that JNK1 is a novel regulator of feeding by antagonizing glucocorticoid function in AgRP neurons. Paradoxically, JNK1 mutant mice feed less and lose more weight upon central administration of insulin, suggesting that JNK1 antagonizes insulin function in the brain. Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions.

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Choi, Hong Seok, Ann M. Bode, Jung-Hyun Shim, Sung-Young Lee, and Zigang Dong. "c-Jun N-Terminal Kinase 1 Phosphorylates Myt1 To Prevent UVA-Induced Skin Cancer." Molecular and Cellular Biology 29, no. 8 (February 9, 2009): 2168–80. http://dx.doi.org/10.1128/mcb.01508-08.

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ABSTRACT The c-Jun N-terminal kinase (JNK) signaling pathway is known to mediate both survival and apoptosis of tumor cells. Although JNK1 and JNK2 have been shown to differentially regulate the development of skin cancer, the underlying mechanistic basis remains unclear. Here, we demonstrate that JNK1, but not JNK2, interacts with and phosphorylates Myt1 ex vivo and in vitro. UVA induces substantial apoptosis in JNK wild-type (JNK +/+) or JNK2-deficient (JNK2 −/−) mouse embryonic fibroblasts but has no effect on JNK1-deficient (JNK1 −/−) cells. In addition, UVA-induced caspase-3 cleavage and DNA fragmentation were suppressed by the knockdown of human Myt1 in skin cancer cells. JNK1 deficiency results in suppressed Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA irradiation. In contrast, the absence of JNK2 induces Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA. The overexpression of JNK1 with Myt1 promotes cellular apoptosis during the early embryonic development of Xenopus laevis, whereas the presence of JNK2 reduces the phenotype of Myt1-induced apoptotic cell death. Most importantly, JNK1 −/− mice developed more UVA-induced papillomas than either JNK +/+ or JNK2 −/− mice, which was associated with suppressed Myt1 phosphorylation and decreased caspase-3 cleavage. Taken together, these data provide mechanistic insights into the distinct roles of the different JNK isoforms, specifically suggesting that the JNK1-mediated phosphorylation of Myt1 plays an important role in UVA-induced apoptosis and the prevention of skin carcinogenesis.

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LoGrasso, Philip, and Theodore Kamenecka. "Inhibitors of c-jun-N-Terminal Kinase (JNK)." Mini-Reviews in Medicinal Chemistry 8, no. 8 (July 1, 2008): 755–66. http://dx.doi.org/10.2174/138955708784912120.

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Ma, Hongpeng. "Relationship Between c-Jun N-terminal Kinase and Depression." E3S Web of Conferences 185 (2020): 03029. http://dx.doi.org/10.1051/e3sconf/202018503029.

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Depression is one of the most common emotional disorders. The cause of depression is still not clear. C-Jun N-terminal kinase (JNK) is one number of mitogen activated protein kinase (MAPK) family, which is closely related to the occurrence of many diseases. At present, it is believed that JNK plays an important role in the parthenogenesis of depression, but the specific mechanism is not clear. This review will focus on the possible mechanism of JNK protein and JNK signaling pathway affecting the parthenogenesis of depression.

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Ye, Zhiqiang, Yuxian Chen, Rongkai Zhang, Haitao Dai, Chun Zeng, Hua Zeng, Hui Feng, Gengheng Du, Hang Fang, and Daozhang Cai. "c-Jun N-terminal kinase – c-Jun pathway transactivates Bim to promote osteoarthritis." Canadian Journal of Physiology and Pharmacology 92, no. 2 (February 2014): 132–39. http://dx.doi.org/10.1139/cjpp-2013-0228.

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Osteoarthritis (OA) is a chronic degenerative joint disorder. Previous studies have shown abnormally increased apoptosis of chondrocytes in patients and animal models of OA. TNF-α and nitric oxide have been reported to induce chondrocyte ageing; however, the mechanism of chondrocyte apoptosis induced by IL-1β has remained unclear. The aim of this study is to identify the role of the c-Jun N-terminal kinase (JNK) – c-Jun pathway in regulating induction of Bim, and its implication in chondrocyte apoptosis. This study showed that Bim is upregulated in chondrocytes obtained from the articular cartilage of OA patients and in cultured mouse chondrocytes treated with IL-1β. Upregulation of Bim was found to be critical for chondrocyte apoptosis induced by IL-1β, as revealed by the genetic knockdown of Bim, wherein apoptosis was greatly reduced in the chondrocytes. Moreover, activation of the JNK–c-Jun pathway was observed under IL-1β treatment, as indicated by the increased expression levels of c-Jun protein. Suppression of the JNK–c-Jun pathway, using chemical inhibitors and RNA interference, inhibited the Bim upregulation induced by IL-1β. These findings suggest that the JNK–c-Jun pathway is involved in the upregulation of Bim during OA and that the JNK–c-Jun–Bim pathway is vital for chondrocyte apoptosis.

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See, Raymond H., and Yang Shi. "Adenovirus E1B 19,000-Molecular-Weight Protein Activates c-Jun N-Terminal Kinase and c-Jun-Mediated Transcription." Molecular and Cellular Biology 18, no. 7 (July 1, 1998): 4012–22. http://dx.doi.org/10.1128/mcb.18.7.4012.

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ABSTRACT Adenovirus E1B proteins (19,000-molecular-weight [19K] and 55K proteins) inhibit apoptosis and cooperate with adenovirus E1A to induce full oncogenic transformation of primary cells. The E1B 19K protein has previously been shown to be capable of activating transcription; however, the underlying mechanisms are unclear. Here, we show that adenovirus infection activates the c-Jun N-terminal kinase (JNK) and that the E1B gene products are necessary for adenovirus to activate JNK. In transfection assays, we show that the E1B 19K protein is sufficient to activate JNK and can strongly induce c-Jun-dependent transcription. Mapping studies show that the C-terminal portion of E1B 19K is necessary for induction of c-Jun-mediated transcription. Using dominant-negative mutants of several kinases upstream of JNK, we show that MEKK1 and MKK4, but not Ras, are involved in the induction of JNK activity by adenovirus infection. The same dominant-negative kinase mutants also block the ability of E1B 19K to induce c-Jun-mediated transcription. Taken together, these results suggest that E1B 19K may utilize the MEKK1-MKK4-JNK signaling pathway to activate c-Jun-dependent transcription and demonstrate a novel, kinase-activating activity of E1B 19K that may underlie its ability to regulate transcription.

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Smith, Abigail O., Julie A. Jonassen, Kenley M. Preval, Roger J. Davis, and Gregory J. Pazour. "c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease." PLOS Genetics 17, no. 12 (December 28, 2021): e1009711. http://dx.doi.org/10.1371/journal.pgen.1009711.

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Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

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Siddiqui, M. Arshad, and Panduranga A. Reddy. "Small Molecule JNK (c-Jun N-Terminal Kinase) Inhibitors." Journal of Medicinal Chemistry 53, no. 8 (April 22, 2010): 3005–12. http://dx.doi.org/10.1021/jm9003279.

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Sluss, H. K., T. Barrett, B. Dérijard, and R. J. Davis. "Signal transduction by tumor necrosis factor mediated by JNK protein kinases." Molecular and Cellular Biology 14, no. 12 (December 1994): 8376–84. http://dx.doi.org/10.1128/mcb.14.12.8376-8384.1994.

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JNK protein kinases are distantly related to mitogen-activated protein kinases (ERKs) and are activated by dual phosphorylation on Tyr and Thr. The JNK protein kinase group includes the 46-kDa isoform JNK1. Here we describe the molecular cloning of a second member of the JNK group, the 55-kDa protein kinase JNK2. The activities of both JNK isoforms are markedly increased by exposure of cells to UV radiation. Furthermore, JNK protein kinase activation is observed in cells treated with tumor necrosis factor. Although both JNK isoforms phosphorylate the NH2-terminal activation domain of the transcription factor c-Jun, the activity of JNK2 was approximately 10-fold greater than that of JNK1. This difference in c-Jun phosphorylation correlates with increased binding of c-Jun to JNK2 compared with JNK1. The distinct in vitro biochemical properties of these JNK isoforms suggest that they may have different functions in vivo. Evidence in favor of this hypothesis was obtained from the observation that JNK1, but not JNK2, complements a defect in the expression of the mitogen-activated protein kinase HOG1 in the yeast Saccharomyces cerevisiae. Together, these data indicate a role for the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation.

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Sluss, H. K., T. Barrett, B. Dérijard, and R. J. Davis. "Signal transduction by tumor necrosis factor mediated by JNK protein kinases." Molecular and Cellular Biology 14, no. 12 (December 1994): 8376–84. http://dx.doi.org/10.1128/mcb.14.12.8376.

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JNK protein kinases are distantly related to mitogen-activated protein kinases (ERKs) and are activated by dual phosphorylation on Tyr and Thr. The JNK protein kinase group includes the 46-kDa isoform JNK1. Here we describe the molecular cloning of a second member of the JNK group, the 55-kDa protein kinase JNK2. The activities of both JNK isoforms are markedly increased by exposure of cells to UV radiation. Furthermore, JNK protein kinase activation is observed in cells treated with tumor necrosis factor. Although both JNK isoforms phosphorylate the NH2-terminal activation domain of the transcription factor c-Jun, the activity of JNK2 was approximately 10-fold greater than that of JNK1. This difference in c-Jun phosphorylation correlates with increased binding of c-Jun to JNK2 compared with JNK1. The distinct in vitro biochemical properties of these JNK isoforms suggest that they may have different functions in vivo. Evidence in favor of this hypothesis was obtained from the observation that JNK1, but not JNK2, complements a defect in the expression of the mitogen-activated protein kinase HOG1 in the yeast Saccharomyces cerevisiae. Together, these data indicate a role for the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation.

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Zohn, I. E., H. Yu, X. Li, A. D. Cox, and H. S. Earp. "Angiotensin II stimulates calcium-dependent activation of c-Jun N-terminal kinase." Molecular and Cellular Biology 15, no. 11 (November 1995): 6160–68. http://dx.doi.org/10.1128/mcb.15.11.6160.

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In GN4 rat liver epithelial cells, angiotensin II (Ang II) and other agonists which activate phospholipase C stimulate tyrosine kinase activity in a calcium-dependent, protein kinase C (PKC)-independent manner. Since Ang II also produces a proliferative response in these cells, we investigated downstream signaling elements traditionally linked to growth control by tyrosine kinases. First, Ang II, like epidermal growth factor (EGF), stimulated AP-1 binding activity in a PKC-independent manner. Because increases in AP-1 can reflect induction of c-Jun and c-Fos, we examined the activity of the mitogen-activated protein (MAP) kinase family members Erk-1 and -2 and the c-Jun N-terminal kinase (JNK), which are known to influence c-Jun and c-Fos transcription. Ang II stimulated MAP kinase (MAPK) activity but only approximately 50% as effectively as EGF; again, these effects were independent of PKC. Ang II also produced a 50- to 200-fold activation of JNK in a PKC-independent manner. Unlike its smaller effect on MAPK, Ang II was approximately four- to sixfold more potent in activating JNK than EGF was. Although others had reported a lack of calcium ionophore-stimulated JNK activity in lymphocytes and several other cell lines, we examined the role of calcium in GN4 cells. The following results suggest that JNK activation in rat liver epithelial cells is at least partially Ca(2+) dependent: (i) norepinephrine and vasopressin hormones that increase inositol 1,4,5-triphosphate stimulated JNK; (ii) both thapsigargin, a compound that produces an intracellular Ca(2+) signal, and Ca(2+) ionophores stimulated a dramatic increase in JNK activity (up to 200-fold); (iii) extracellular Ca(2+) chelation with ethylene glycol tetraacetic acid (EGTA) inhibited JNK activation by ionophore and intracellular chelation with 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl-ester (BAPTA-AM) partially inhibited JNK activation by Ang II or thapsigargin; and (iv) JNK activation by Ang II was inhibited by pretreatment of cells with thapsigargin and EGTA, a procedure which depletes intracellular Ca(2+) stores. JNK activation following Ang II stimulation did not involve calmodulin; either W-7 nor calmidizolium, in concentrations sufficient to inhibit Ca(2+)/calmodulin-dependent kinase II, blocked JNK activation by Ang II. In contrast, genistein, in concentrations sufficient to inhibit Ca(2+)-dependent tyrosine phosphorylation, prevented Ang II and thapsigargin-induced JNK activation. In summary, in GN4 rat liver epithelial cells, Ang II stimulates JNK via a novel Ca(2+)-dependent pathway. The inhibition by genistein suggest that Ca(2+)-dependent tyrosine phosphorylation may modulate the JNK pathway in a cell type-specific manner, particularly in cells with a readily detectable Ca(2+)-regulated tyrosine kinase.

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Yeap, Yvonne Y. C., Ivan H. W. Ng, Bahareh Badrian, Tuong-Vi Nguyen, Yan Y. Yip, Amardeep S. Dhillon, Steven E. Mutsaers, John Silke, Marie A. Bogoyevitch, and Dominic C. H. Ng. "c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18." Biochemical Journal 430, no. 2 (August 13, 2010): 345–54. http://dx.doi.org/10.1042/bj20100425.

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The JNKs (c-Jun N-terminal kinases) are stress-activated serine/threonine kinases that can regulate both cell death and cell proliferation. We have developed a cell system to control JNK re-expression at physiological levels in JNK1/2-null MEFs (murine embryonic fibroblasts). JNK re-expression restored basal and stress-activated phosphorylation of the c-Jun transcription factor and attenuated cellular proliferation with increased cells in G1/S-phase of the cell cycle. To explore JNK actions to regulate cell proliferation, we evaluated a role for the cytosolic protein, STMN (stathmin)/Op18 (oncoprotein 18). STMN, up-regulated in a range of cancer types, plays a crucial role in the control of cell division through its regulation of microtubule dynamics of the mitotic spindle. In JNK1/2-null or c-Jun-null MEFs or cells treated with c-Jun siRNA (small interfering RNA), STMN levels were significantly increased. Furthermore, a requirement for JNK/cJun signalling was demonstrated by expression of wild-type c-Jun, but not a phosphorylation-defective c-Jun mutant, being sufficient to down-regulate STMN. Critically, shRNA (small hairpin RNA)-directed STMN down-regulation in JNK1/2-null MEFs attenuated proliferation. Thus JNK/c-Jun regulation of STMN levels provides a novel pathway in regulation of cell proliferation with important implications for understanding the actions of JNK as a physiological regulator of the cell cycle and tumour suppressor protein.

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Guan, Z., T. Tetsuka, L. D. Baier, and A. R. Morrison. "Interleukin-1 beta activates c-jun NH2-terminal kinase subgroup of mitogen-activated protein kinases in mesangial cells." American Journal of Physiology-Renal Physiology 270, no. 4 (April 1, 1996): F634—F641. http://dx.doi.org/10.1152/ajprenal.1996.270.4.f634.

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We investigated whether JNK is activated by interleukin-1 beta (IL-1 beta) in mesangial cells. We performed in-gel kinase assays with His-c-jun-(1-79), which contains the amino-terminal activation domain of c-jun and a mutant His-c-jun in which Ser-63 and Ser-73 of His-c-jun were mutated to Ala as the substrates. JNK1 (p45) and JNK2 (p54) isoforms phosphorylated His-c-jun in mesangial cells. IL-1 beta produced a time- and concentration-dependent increase in JNK activity. IL-1 beta did not phosphorylated the mutant, His-c-jun. The IL-1 beta-activated JNK activity was independent of serum and suppressed by neither tyrosine kinase inhibitors nor protein kinase C inhibitors. JNK was also stimulated by anisomycin and okadaic acid but not by phorbol 12-myristate 13-acetate. The protein synthesis inhibitors and okadaic acid potentiated the IL-1 beta-induced JNK activity. Together, these studies indicate that the novel JNK group of protein kinases may play an important role in the signal transduction pathway initiated by proinflammatory cytokines, such as IL-1 beta in mesangial cells.

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Hirasawa, Noriyasu, Yukako Sato, Yuhko Fujita, Suetsugu Mue, and Kazuo Ohuchi. "Inhibition by Dexamethasone of Antigen-Induced c-Jun N-Terminal Kinase Activation in Rat Basophilic Leukemia Cells." Journal of Immunology 161, no. 9 (November 1, 1998): 4939–43. http://dx.doi.org/10.4049/jimmunol.161.9.4939.

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Abstract Antigen stimulation of IgE-sensitized rat basophilic leukemia RBL-2H3 cells induced activation of c-Jun N-terminal kinase (JNK) within a few minutes with maximum activity attained 40 min later. The increase in JNK activity was accompanied with an increase in phosphorylation of c-Jun in the cells. The Ag-induced JNK activation was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin (10–100 nM) and LY 294002 (100 μM) but not by the protein kinase C inhibitors calphostin C (1 and 3 μM) and Ro 31-8425 (1 and 3 μM). Pretreatment with dexamethasone (10 and 100 nM) for 18 h inhibited the Ag-induced increase in JNK activity in a concentration-dependent manner. At least 6 h of preincubation with dexamethasone was necessary to inhibit the Ag-induced JNK activation. The phosphorylation of c-Jun induced by the Ag stimulation was reduced by pretreatment with dexamethasone without reduction of the content of c-Jun protein. The Ag-induced activation of the JNK kinase kinase mitogen-activated protein kinase-extracellular signal-regulated kinase kinase-1 was also inhibited by pretreatment with dexamethasone at 10 and 100 nM. These findings indicate that dexamethasone reduces JNK protein level and inhibits the Ag-induced activation of JNK resulting in the inhibition of c-Jun phosphorylation.

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Jones, Emma V., Mark J. Dickman, and Alan J. Whitmarsh. "Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase." Biochemical Journal 405, no. 3 (July 13, 2007): 617–23. http://dx.doi.org/10.1042/bj20061778.

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The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

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Moon, Il-Soo. "Expression of c-Jun N-Terminal Kinase (JNK)-Interacting Protein (JIP) in Cultured Rat Hippocampal Neurons." Journal of Life Science 17, no. 12 (December 30, 2007): 1627–33. http://dx.doi.org/10.5352/jls.2007.17.12.1627.

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Tai, Tina Y., Lindsay N. Warner, Terrance D. Jones, Sangwook Jung, David W. Skyrud, and Nicholas P. Poolos. "Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition." Epilepsy & Behavior 46 (May 2015): 55. http://dx.doi.org/10.1016/j.yebeh.2015.02.054.

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Schwertfeger, Kathryn L., Seija Hunter, Lynn E. Heasley, Valerie Levresse, Ronald P. Leon, James DeGregori, and Steven M. Anderson. "Prolactin Stimulates Activation of c-jun N-Terminal Kinase (JNK)." Molecular Endocrinology 14, no. 10 (October 1, 2000): 1592–602. http://dx.doi.org/10.1210/mend.14.10.0536.

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Li, Gang. "Recent Advances in c-Jun N-Terminal Kinase (JNK) Inhibitors." Current Medicinal Chemistry 28, no. 3 (2021): 607–27. http://dx.doi.org/10.2174/1875533xmta0tmzuv4.

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Min, Robert W. M., Filbert W. M. Aung, Bryant Liu, Aliza Arya, and Sanda Win. "Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease." Biomedicines 10, no. 8 (August 20, 2022): 2035. http://dx.doi.org/10.3390/biomedicines10082035.

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Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially c-Jun-N-terminal kinases (JNKs), leads to unwanted genetic and epi-genetic modifications in addition to the metabolic stress adaptation in hepatocytes. A mechanism of sustained P-JNK activation was identified in acute and chronic liver diseases, suggesting an important role of aberrant JNK activation in NASH. Therefore, modulation of JNK activation, rather than targeting JNK protein levels, is a plausible therapeutic application for the treatment of chronic liver disease.

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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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KATZ, Sigal, and Ami ARONHEIM. "Differential targeting of the stress mitogen-activated protein kinases to the c-Jun dimerization protein 2." Biochemical Journal 368, no. 3 (December 15, 2002): 939–45. http://dx.doi.org/10.1042/bj20021127.

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The mitogen-activated kinases are structurally related proline-directed serine/threonine kinases that phosphorylate similar phosphoacceptor sites and yet, in vivo, they exhibit stringent substrate specificity. Specific targeting domains (kinase docking domains) facilitate kinase—substrate interaction and play a major role in substrate specificity determination. The c-Jun N-terminal kinase (JNK) consensus docking domain comprises of a KXXK/RXXXXLXL motif located in the Δ-domain of the c-Jun N-terminal to the phosphoacceptor site. The c-Jun dimerization protein 2 is phosphorylated by JNK on Thr-148. Activating transcription factor 3 (ATF3) is a basic leucine zipper protein which is highly homologous to c-Jun dimerization protein 2 (JDP2), especially within the threonine/proline phosphoacceptor site, Thr-148. Nevertheless, ATF3 does not serve as a JNK substrate in vitro or in vivo. Using ATF3 and JDP2 protein chimaeras, we mapped the JNK-docking domain within JDP2. Although a JNK consensus putative docking site is located within the JDP2 leucine zipper motif, this domain does not function to recruit JNK to JDP2. A novel putative docking domain located C-terminally to the JDP2 phosphoacceptor site was identified. This domain, when fused to the ATF3 heterologous phosphoacceptor site, can direct its phosphorylation by JNK. In addition, although the novel JNK-docking domain was found to be necessary for p38 phosphorylation of JDP2 on Thr-148, it was not sufficient to confer JDP2 phosphorylation by the p38 kinase.

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Ventura, Juan-Jose, Norman J. Kennedy, Jennifer A. Lamb, Richard A. Flavell, and Roger J. Davis. "c-Jun NH2-Terminal Kinase Is Essential for the Regulation of AP-1 by Tumor Necrosis Factor." Molecular and Cellular Biology 23, no. 8 (April 15, 2003): 2871–82. http://dx.doi.org/10.1128/mcb.23.8.2871-2882.2003.

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ABSTRACT The c-Jun NH2-terminal kinase (JNK) is activated by the cytokine tumor necrosis factor (TNF). This pathway is implicated in the regulation of AP-1-dependent gene expression by TNF. To examine the role of the JNK signaling pathway, we compared the effects of TNF on wild-type and Jnk1 −/− Jnk2 −/− murine embryo fibroblasts. We show that JNK is required for the normal regulation of AP-1 by TNF. The JNK-deficient cells exhibited decreased expression of c-Jun, JunD, c-Fos, Fra1, and Fra2; decreased phosphorylation of c-Jun and JunD; and decreased AP-1 DNA binding activity. The JNK-deficient cells also exhibited defects in the regulation of the AP-1-related transcription factor ATF2. These changes were associated with marked defects in TNF-regulated gene expression. The JNK signal transduction pathway is therefore essential for AP-1 transcription factor regulation in cells exposed to TNF.

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Pirianov, Grisha, David A. MacIntyre, Yun Lee, Simon N. Waddington, Vasso Terzidou, Huseyin Mehmet, and Phillip R. Bennett. "Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality." REPRODUCTION 150, no. 4 (October 2015): 269–77. http://dx.doi.org/10.1530/rep-15-0258.

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Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain.

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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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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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Zhong, Shuping, Jody Fromm, and Deborah L. Johnson. "TBP Is Differentially Regulated by c-Jun N-Terminal Kinase 1 (JNK1) and JNK2 through Elk-1, Controlling c-Jun Expression and Cell Proliferation." Molecular and Cellular Biology 27, no. 1 (January 1, 2007): 54–64. http://dx.doi.org/10.1128/mcb.01365-06.

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ABSTRACT Emerging evidence supports the idea that the c-Jun N-terminal kinases (JNKs) possess overlapping but distinct functions. The potential roles of the ubiquitously expressed JNK1 and JNK2 in regulating expression of the central transcription initiation factor, TATA-binding protein (TBP), were examined. Relative to wild-type fibroblasts, TBP was decreased in Jnk1 −/− cells and increased in Jnk2 −/− cells. Similarly, reduction of JNK1 in human hepatoma cells decreased TBP expression, whereas reduction of JNK2 enhanced it. JNK-mediated regulation of TBP expression occurs at the transcriptional level through their ability to target Elk-1, which directly regulates the TBP promoter in response to epidermal growth factor stimulation. JNK1 increases, whereas JNK2 decreases, the phosphorylation state of Elk-1, which differentially affects Elk-1 occupancy at a defined site within the TBP promoter. These JNK-mediated alterations in TBP expression, alone, serve to regulate c-Jun expression and fibroblast proliferation rates. These studies uncovered several new molecular events that distinguish the functions of JNK1 and JNK2 that are critical for their regulation of cellular proliferation.

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Anfinogenova, Nina D., Mark T. Quinn, Igor A. Schepetkin, and Dmitriy N. Atochin. "Alarmins and c-Jun N-Terminal Kinase (JNK) Signaling in Neuroinflammation." Cells 9, no. 11 (October 24, 2020): 2350. http://dx.doi.org/10.3390/cells9112350.

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Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group box protein 1, S100 proteins, heat shock proteins, nucleic acids, histones, nucleosomes, and monosodium urate microcrystals are thought to be alarmins. They are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors. Being principal sterile inflammation triggering agents, alarmins are considered biomarkers and therapeutic targets. They are recognized by host cells and prime the innate immune system toward cell death and distress. In stroke, alarmins act as mediators initiating the inflammatory response after the release from the cellular components of the infarct core and penumbra. Increased c-Jun N-terminal kinase (JNK) phosphorylation may be involved in the mechanism of stress-induced release of alarmins. Putative crosstalk between the alarmin-associated pathways and JNK signaling seems to be inherently interwoven. This review outlines the role of alarmins/JNK-signaling in cerebral neurovascular inflammation and summarizes the complex response of cells to alarmins. Emerging anti-JNK and anti-alarmin drug treatment strategies are discussed.

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Fritz, G., and B. Kaina. "Activation of c-Jun N-Terminal Kinase 1 by UV Irradiation Is Inhibited by Wortmannin without Affecting c-jun Expression." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 1768–74. http://dx.doi.org/10.1128/mcb.19.3.1768.

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ABSTRACT Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases is an early response of cells upon exposure to DNA-damaging agents. JNK-mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulation of JNK1 activity is not a general early response of cells exposed to genotoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as with methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs such as mafosfamide, mitomycin C,N-hydroxyethyl-N-chloroethylnitrosourea, and treosulfan did not elicit this response. The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2). To investigate the significance of JNK1 for transactivation of c-jun, we analyzed the effect of UV irradiation on c-jun expression under conditions of wortmannin-mediated inhibition of UV-induced stimulation of JNK1. Neither the UV-induced increase in c-jun mRNA, c-Jun protein, and AP-1 binding nor the activation of the collagenase and c-junpromoters was affected by wortmannin. In contrast, the mitogen-activated protein kinase/ERK kinase inhibitor PD98056, which blocked ERK2 but not JNK1 activation by UV irradiation, impaired UV-driven c-Jun protein induction and AP-1 binding. Based on the data, we suggest that JNK1 stimulation is not essential for transactivation of c-jun after UV exposure, whereas activation of ERK2 is required for UV-induced signaling leading to elevated c-junexpression.

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Busquets, Oriol, Miren Ettcheto, Amanda Cano, Patricia R. Manzine, Elena Sánchez-Lopez, Triana Espinosa-Jiménez, Ester Verdaguer, et al. "Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment." International Journal of Molecular Sciences 21, no. 1 (December 30, 2019): 255. http://dx.doi.org/10.3390/ijms21010255.

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Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed.

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Lai, Benjamin, Chien-Hsiang Wu, and Jenn-Haung Lai. "Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis." Cells 9, no. 11 (November 12, 2020): 2466. http://dx.doi.org/10.3390/cells9112466.

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The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.

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Hepp Rehfeldt, Stephanie Cristine, Fernanda Majolo, Márcia Inês Goettert, and Stefan Laufer. "c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases." International Journal of Molecular Sciences 21, no. 24 (December 18, 2020): 9677. http://dx.doi.org/10.3390/ijms21249677.

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Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.

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Min, W., and J. S. Pober. "TNF initiates E-selectin transcription in human endothelial cells through parallel TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways." Journal of Immunology 159, no. 7 (October 1, 1997): 3508–18. http://dx.doi.org/10.4049/jimmunol.159.7.3508.

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Abstract TNF acts on the E-selectin gene promoter at three kappa B elements and at a variant cAMP-responsive element that binds ATF2/c-Jun. In human endothelial cells, TNF rapidly induces N-terminal domain phosphorylation of both c-Jun and ATF2. Transient overexpression of N-terminal truncated c-Jun or catalytically inactive Jun N-terminal kinase (JNK) 1 and 2 inhibits TNF-induced transcription of an E-selectin but not a kappa B promoter-reporter gene. Transient overexpression of the TRAF2 adaptor protein can activate NF-kappaB and endogenous JNK, whereas N-terminal truncated TRAF2 protein blocks TNF-induced NF-kappa B and JNK activation as well as E-selectin promoter-reporter gene transcription. Transient overexpression of RAC1 or CDC42, but not RAS, constitutively activates JNK and augments TNF-induced E-selectin transcription. Finally, transient overexpression of catalytically inactive JNK or truncated TRAF2 partially inhibits endogenous E-selectin protein expression in human endothelial cells. These data suggest that TNF activates parallel TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways to initiate E-selectin transcription.

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BUTTERFIELD, Laura, Eve ZENTRICH, Andrew BEEKMAN, and Lynn E. HEASLEY. "Stress- and cell type-dependent regulation of transfected c-Jun N-terminal kinase and mitogen-activated protein kinase kinase isoforms." Biochemical Journal 338, no. 3 (March 8, 1999): 681–86. http://dx.doi.org/10.1042/bj3380681.

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The cJun N-terminal kinases (JNKs) are encoded by three genes generating ten protein kinase polypeptides and are activated in settings of cell stress, mitogenesis, differentiation and morphogenesis. The specific role of the JNK family members in these diverse cell programmes is largely undefined. In this study, we tested the hypothesis that individual JNK isoforms would exhibit distinct patterns of regulation within cells. The cDNAs encoding five haemagglutinin (HA)-tagged JNK isoforms (p46JNK1α, p54JNK2α, p54JNK2β, p46JNK3 and p54JNK3) were expressed in cultured rat PC12 phaeochromocytoma cells and human small-cell lung cancer (SCLC) cells by retrovirus-mediated gene transfer. In addition, HA-tagged forms of the dual-specificity mitogen-activated protein kinase kinases (MKKs), MKK4 and MKK7, which are specific activators of the JNK enzymes, were similarly expressed. Reverse transcription and PCR revealed that JNK3 is endogenously expressed in SCLC cells, but not in either chromaffin or neuronally differentiated PC12 cells. MKK4 and MKK7 were endogenously expressed in both PC12 cells and SHP77 cells. Immunoprecipitation and analysis of the JNKs expressed in SCLC cells revealed strong stimulation of all five JNK isoforms by UV radiation. Hypertonic stress, elicited by mannitol, also significantly stimulated these same JNKs, although the JNK3 isoforms were most strongly activated. In PC12 cell transfectants, however, selective and equal activation of p54JNK2α and p54JNK3 by UV and osmotic stress was observed, with little or no activation of JNK1α or JNK2β. In contrast with the broad activation of the JNK enzymes by UV in SCLC cells, only HA-MKK4 was stimulated by UV exposure in these cells, whereas osmotic stress stimulated both HA-MKK4 and HA-MKK7. These findings indicate selective activation of JNK and MKK isoforms in a manner that is dependent upon the specific cell stress and the cell type.

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Izadi, Hooman, Amirreza T. Motameni, Tonya C. Bates, Elias R. Olivera, Vega Villar-Suarez, Ila Joshi, Renu Garg, et al. "c-Jun N-Terminal Kinase 1 Is Required for Toll-Like Receptor 1 Gene Expression in Macrophages." Infection and Immunity 75, no. 10 (July 30, 2007): 5027–34. http://dx.doi.org/10.1128/iai.00492-07.

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ABSTRACT The regulation of innate immune responses to pathogens occurs through the interaction of Toll-like receptors (TLRs) with pathogen-associated molecular patterns and the activation of several signaling pathways whose contribution to the overall innate immune response to pathogens is poorly understood. We demonstrate a mechanism of control of murine macrophage responses mediated by TLR1/2 heterodimers through c-Jun N-terminal kinase 1 (JNK1) activity. JNK controls tumor necrosis factor alpha production and TLR-mediated macrophage responses to Borrelia burgdorferi, the causative agent of Lyme disease, and the TLR1/TLR2-specific agonist PAM3CSK4. JNK1, but not JNK2, activity regulates the expression of the tlr1 gene in the macrophage cell line RAW264.7, as well as in primary CD11b+ cells. We also show that the proximal promoter region of the human tlr1 gene contains an AP-1 binding site that is subjected to regulation by the kinase and binds two complexes that involve the JNK substrates c-Jun, JunD, and ATF-2. These results demonstrate that JNK1 regulates the response to TLR1/2 ligands and suggest a positive feedback loop that may serve to increase the innate immune response to the spirochete.

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Taniguchi, Cullen M., José O. Aleman, Kohjiro Ueki, Ji Luo, Tomoichiro Asano, Hideaki Kaneto, Gregory Stephanopoulos, Lewis C. Cantley, and C. Ronald Kahn. "The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance." Molecular and Cellular Biology 27, no. 8 (February 5, 2007): 2830–40. http://dx.doi.org/10.1128/mcb.00079-07.

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ABSTRACT Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85α regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85α regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85α regulatory subunit. Thus, p85α plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.

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Bare, Yohanes, Mansur S, Sri Sulystyaningsih Natalia Daeng Tiring, Dewi Ratih Tirto Sari, and Andri Maulidi. "Virtual Screening: Prediksi potensi 8-shogaol terhadap c-Jun N-Terminal Kinase (JNK)." Jurnal Penelitian dan Pengkajian Ilmu Pendidikan: e-Saintika 4, no. 1 (March 5, 2020): 1. http://dx.doi.org/10.36312/e-saintika.v4i1.157.

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JNK adalah gen yang berperan dalam metabolisme DMT2. Dalam pengobatan T2DM digunakan JNK sebagai potensi terapi dengan menggunakan bahan alam. 8-shogaol adalah komponen kimia yang terkandung dalam jahe yang memiliki aktivitas antioksidan. Tujuan dari penelitina ini adalah menginversitagasi dan menganalisis peran 8-shogaol terhadap JNK. Protein JNK (ID: 464Y) diperoleh dari Protein Data Bank dan ligan 8-shogaol (CID:6442560 ) didapat dari pubchem. Ligan dan protein didocking menggunakan Hex 8.0.0. File dalam bentuk pdb divisualtisasi dan analisis menggunakan Discovery Studio Client 4.1 software. Interaksi ligan-protein menunjukan ikatan hidrogen pada residu asam amino LYS93 dan van der Waals pada 18 residu asam amino dengan energi ikatan-289.68cal/mol. Interkasi ini berpotensi sebagai penghambat kerja JNK dan dapat digunakan dalam terapi DMT2.Virtual screening: potential prediction of 8-shogaol againts c-Jun N-Terminal Kinase (JNK)AbstractJNK is one of gene that has a role in T2DM condition. To curve T2DM use JNK as potential healing using natural compounds. Eight-shogaol which found in ginger has function as a antioxidant.. The aim of the research is to investigate and analyze role 8-shogaol againts JNK. Protein JNK (ID: 464Y) was taken from Protein Data Bank and ligand 8-shogaol (CID:6442560 ) acquired from pubchem. Ligand and protein model were docked using Hex 8.0.0 software. Visualization and analysis molecular interactions by the Discovery Studio Client 4.1 software. Interaction ligand-protein showed one hydrogen bond in amino acid residue LYS93 and formed van der Waals in eighteen amino acid residues which energy binding -289.68cal/mol. This interaction has a potential to inhibit JNK role and lead to therapy T2DM.

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Gaarde, William A., Tony Hunter, Helen Brady, Brion W. Murray, and Mark E. Goldman. "Development of a Nonradioactive, Time-Resolved Fluorescence Assay for the Measurement of Jun N-Terminal Kinase Activity." Journal of Biomolecular Screening 2, no. 4 (June 1997): 213–23. http://dx.doi.org/10.1177/108705719700200406.

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Activated transcription factor AP-1 is composed of c-Jun homodimers or c-Jun/c-Fos heterodimers and mediates expression of several gene products that have been implicated in disease pathogenesis. Activation of AP-1 is dependent on phosphorylation of c-Jun by Jun N-terminal kinase (JNK). Therefore, identification of inhibitors of JNK-mediated phosphorylation of c-Jun may lead to a novel class of therapeutics. A nonradioactive, high-through-put, time-resolved fluorescence assay was developed to measure and identify inhibitors of JNK activity. This assay utilized a lanthanide (europium)-labeled antibody that was specific for N-terminally phosphorylated c-Jun. The optimized europium-based assay was approximately 15-fold more sensitive compared to a similar 32P-based JNK assay. Compounds that were identified as inhibitors of JNK using the europium-based assay also inhibited JNK activity in the 32P-based assay with similar IC50 values. The europium-based JNK assay eliminates the contamination problems associated with the use of radioactivity. The sensitivity and safety of the europium-based assay make it amenable to robotics that will significantly increase screening throughput.

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Clarke, Melanie, Rowan Pentz, Jessica Bobyn, and Shawn Hayley. "Stressor-Like Effects of c-Jun N-Terminal Kinase (JNK) Inhibition." PLoS ONE 7, no. 8 (August 29, 2012): e44073. http://dx.doi.org/10.1371/journal.pone.0044073.

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Ju, Youn H., and Chang H. Cho. "Effects of c-Jun N-Terminal Kinase(JNK) on Neurite Growth." Otolaryngology–Head and Neck Surgery 147, no. 2_suppl (August 2012): P206—P207. http://dx.doi.org/10.1177/0194599812451426a258.

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Bogoyevitch, Marie A., Kevin R. W. Ngoei, Teresa T. Zhao, Yvonne Y. C. Yeap, and Dominic C. H. Ng. "c-Jun N-terminal kinase (JNK) signaling: Recent advances and challenges." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1804, no. 3 (March 2010): 463–75. http://dx.doi.org/10.1016/j.bbapap.2009.11.002.

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Kumar, Ashok, Sunil K. Manna, Subhash Dhawan, and Bharat B. Aggarwal. "HIV-Tat Protein Activates c-Jun N-Terminal Kinase and Activator Protein-1." Journal of Immunology 161, no. 2 (July 15, 1998): 776–81. http://dx.doi.org/10.4049/jimmunol.161.2.776.

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Abstract Human immunodeficiency virus-1 tat (HIV-tat) protein, like other proinflammatory cytokines (such as TNF), activates a wide variety of cellular responses, some of which play a critical role in progression of HIV infection. Whether HIV-tat, like TNF, also activates c-Jun N-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 is not known. We show that treatment of human histiocytic lymphoma U937 cells with the HIV-tat protein causes activation of JNK and AP-1 in a time- and dose-dependent manner. Transfection of a T cell line, H9 cells with the HIV-tat gene also resulted in an activation of JNK that was not further increased by treatment of cells with exogenous HIV-tat protein. Neutralizing Ab against HIV-tat inhibited the HIV-tat-mediated JNK activation. The activation of JNK by HIV-tat appears to be mediated through generation of free radical species, since pretreatment of cells with N-acetylcysteine (NAC) abolished the effect. Overall our results demonstrate that HIV-tat activates JNK and AP-1, which may contribute to the pathogenesis of AIDS.

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Xu, Ping, and Roger J. Davis. "c-Jun NH2-Terminal Kinase Is Required for Lineage-Specific Differentiation but Not Stem Cell Self-Renewal." Molecular and Cellular Biology 30, no. 6 (January 11, 2010): 1329–40. http://dx.doi.org/10.1128/mcb.00795-09.

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ABSTRACT The c-Jun NH2-terminal kinase (JNK) is implicated in proliferation. Mice with a deficiency of either the Jnk1 or the Jnk2 genes are viable, but a compound deficiency of both Jnk1 and Jnk2 causes early embryonic lethality. Studies using conditional gene ablation and chemical genetic approaches demonstrate that the combined loss of JNK1 and JNK2 protein kinase function results in rapid senescence. To test whether this role of JNK was required for stem cell proliferation, we isolated embryonic stem (ES) cells from wild-type and JNK-deficient mice. We found that Jnk1 −/− Jnk2 −/− ES cells underwent self-renewal, but these cells proliferated more rapidly than wild-type ES cells and exhibited major defects in lineage-specific differentiation. Together, these data demonstrate that JNK is not required for proliferation or self-renewal of ES cells, but JNK plays a key role in the differentiation of ES cells.

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Lim, Nicholas R., Colleen J. Thomas, Lokugan S. Silva, Yvonne Y. Yeap, Suwan Yap, James R. Bell, Lea M. D. Delbridge, et al. "Cardioprotective 3′,4′-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition." Biochemical Journal 456, no. 2 (November 8, 2013): 149–61. http://dx.doi.org/10.1042/bj20121538.

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3′,4′-Dihydroxyflavonol, a cardioprotective compound that prevents cardiac injury and cell death, targets Ca2+/camodulin-dependent protein kinase II to inhibit the activation of the stress-activated protein kinases, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase.

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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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Journal articles on the topic 'C-Jun N-terminal kinase (JNK)'

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