Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun N-terminal kinases (JNK) play an important role in many physiologic processes induced by numerous stress signals. Each JNK protein appears to have a distinct function in cancer, diabetes, or Parkinson's disease. Herein, we found that licochalcone A, a major phenolic constituent isolated from licorice root, suppressed JNK1 activity but had little effect on JNK2 in vitro activity. Although licochalcone A binds with JIP1 competitively with either JNK1 or JNK2, a computer simulation model showed that after licochalcone A binding, the ATP-binding cleft of JNK1 was distorted more substantially than that of JNK2. This could reduce the affinity of JNK1 more than JNK2 for ATP binding. Furthermore, licochalcone A inhibited JNK1-mediated, but not JNK2-mediated, c-Jun phosphorylation in both ex vivo and in vitro systems. We also observed that in colon and pancreatic cancer cell lines, JNK1 is highly expressed compared with normal cell lines. In cancer cell lines, treatment with licochalcone A or knocking down JNK1 expression suppressed colon and pancreatic cancer cell proliferation and colony formation. The inhibition resulted in G1 phase arrest and apoptosis. Moreover, an in vivo xenograft mouse study showed that licochalcone A treatment effectively suppressed the growth of HCT116 xenografts, without affecting the body weight of mice. These results show that licochalcone A is a selective JNK1 inhibitor. Therefore, we suggest that because of the critical role of JNK1 in colon cancer and pancreatic carcinogenesis, licochalcone A might have preventive or therapeutic potential against these devastating diseases.
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PMID:Licochalcone A, a natural inhibitor of c-Jun N-terminal kinase 1. 2425 17

c-Jun NH2-terminal kinase (JNK)-interacting protein 3 plays an important role in brain-derived neurotrophic factor/tropomyosin-related kinase B (TrkB) anterograde axonal transport. It remains unclear whether JNK-interacting protein 1 mediates similar effects, or whether JNK-interacting protein 1 affects the regulation of TrkB anterograde axonal transport. In this study, we isolated rat embryonic hippocampus and cultured hippocampal neurons in vitro. Coimmunoprecipitation results demonstrated that JNK-interacting protein 1 formed TrkB complexes in vitro and in vivo. Immunocytochemistry results showed that when JNK-interacting protein 1 was highly expressed, the distribution of TrkB gradually increased in axon terminals. However, the distribution of TrkB reduced in axon terminals after knocking out JNK-interacting protein 1. In addition, there were differences in distribution of TrkB after JNK-interacting protein 1 was knocked out compared with not. However, knockout of JNK-interacting protein 1 did not affect the distribution of TrkB in dendrites. These findings confirm that JNK-interacting protein 1 can interact with TrkB in neuronal cells, and can regulate the transport of TrkB in axons, but not in dendrites.
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PMID:Specific effects of c-Jun NH2-terminal kinase-interacting protein 1 in neuronal axons. 2698 Oct 98

The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.
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PMID:JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. 2746 83

Class I histone deacetylase (HDAC) inhibitors block hypertrophy and fibrosis of the heart by suppressing pathological signaling and gene expression programs in cardiac myocytes and fibroblasts. The impact of HDAC inhibition in unstressed cardiac cells remains poorly understood. Here, we demonstrate that treatment of cultured cardiomyocytes with small molecule HDAC inhibitors leads to dramatic induction of c-Jun amino-terminal kinase (JNK)-interacting protein-1 (JIP1) mRNA and protein expression. In contrast to prior findings, elevated levels of endogenous JIP1 in cardiomyocytes failed to significantly alter JNK signaling or cardiomyocyte hypertrophy. Instead, HDAC inhibitor-mediated induction of JIP1 was required to stimulate expression of the kinesin heavy chain family member, KIF5A. We provide evidence for an HDAC-dependent regulatory circuit that promotes formation of JIP1:KIF5A:microtubule complexes that regulate intracellular transport of cargo such as autophagosomes. These findings define a novel role for class I HDACs in the control of the JIP1/kinesin axis in cardiomyocytes, and suggest that HDAC inhibitors could be used to alter microtubule transport in the heart.
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PMID:Class I HDACs control a JIP1-dependent pathway for kinesin-microtubule binding in cardiomyocytes. 2888 67

The c-Jun N-terminal kinases (JNKs) play a wide variety of roles in cellular signaling processes, dictating important, and even divergent, cellular fates. These essential kinases possess docking surfaces distal to their active sites that interact with diverse binding partners, including upstream activators, downstream substrates, and protein scaffolds. Prior studies have suggested that the interactions of certain protein-binding partners with one such JNK docking surface, termed the D-recruitment site (DRS), can allosterically influence the conformational state of the ATP-binding pocket of JNKs. To further explore the allosteric relationship between the ATP-binding pockets and DRSs of JNKs, we investigated how the interactions of the scaffolding protein JIP1, as well as the upstream activators MKK4 and MKK7, are allosterically influenced by the ATP-binding site occupancy of the JNKs. We show that the affinity of the JNKs for JIP1 can be divergently modulated with ATP-competitive inhibitors, with a >50-fold difference in dissociation constant observed between the lowest- and highest-affinity JNK1-inhibitor complexes. Furthermore, we found that we could promote or attenuate phosphorylation of JNK1's activation loop by MKK4 and MKK7, by varying the ATP-binding site occupancy. Given that JIP1, MKK4, and MKK7 all interact with JNK DRSs, these results demonstrate that there is functional allostery between the ATP-binding sites and DRSs of these kinases. Furthermore, our studies suggest that ATP-competitive inhibitors can allosterically influence the intracellular binding partners of the JNKs.
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PMID:Allosteric Modulation of JNK Docking Site Interactions with ATP-Competitive Inhibitors. 3021 40

Heme oxygenase (HO-1), which may be induced by Cobaltic protoporphyrin IX chloride (CoPPIX) or Rosiglitazone (Ros), is a neuroprotective agent that effectively reduces ischemic stroke. Previous studies have shown that the neuroprotective mechanisms of HO-1 are related to JNK signaling. The expression of HO-1 protects cells from death through the JNK signaling pathway. This study aimed to ascertain whether the neuroprotective effect of HO-1 depends on the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and further influences the JNK signal transmission through HO-1. Prior to the ischemia-reperfusion experiment, CoPPIX was injected through the lateral ventricle for 5 consecutive days or Ros was administered via intraperitoneal administration in the week prior to transient ischemia. Our results demonstrated that HO-1 could inhibit the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and could ultimately diminish the phosphorylation of JNK3. Furthermore, the inhibition of JNK3 phosphorylation downregulated the level of p-c-Jun and elevated neuronal cell death in the CA1 of the hippocampus. Taken together, these findings suggested that HO-1 could ameliorate brain injury by regulating the MLK3-MKK7-JNK3 signaling module, which was scaffolded by JIP1 and JNK signaling during cerebral ischemia/reperfusion.
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PMID:The potential role of HO-1 in regulating the MLK3-MKK7-JNK3 module scaffolded by JIP1 during cerebral ischemia/reperfusion in rats. 3041 37


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