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

Immune cell-specific adaptor proteins create various combinations of multiprotein complexes and integrate signals from cell surface receptors to the nucleus, modulating the specificity and selectivity of intracellular signal transduction. Grap2 is a newly identified adaptor protein specifically expressed in lymphoid tissues. This protein shares 40--50% sequence homology in the SH3 and the SH2 domain with Grb2 and Grap. However, the Grap2 protein has a unique 120-amino acid glutamine- and proline-rich domain between the SH2 and C-terminal SH3 domains. The expression of Grap2 is highly restricted to lymphoid organs and T lymphocytes. In order to understand the role of this specific adaptor protein in immune cell signaling and activation, we searched for the Grap2 interacting protein in T lymphocytes. We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells. The interaction was mediated by the carboxyl-terminal SH3 domain of Grap2 with the second proline-rich motif of HPK1. Coexpression of Grap2 with HPK1 not only increased the kinase activity of HPK1 in the cell, but also had an additive effect on HPK1 mediated JNK activation. Furthermore, over expression of Grap2 and HPK1 induced significant transcriptional activation of c-Jun in the JNK signaling pathway and IL-2 gene reporter activity in stimulated Jurkat T cells. Therefore, our data suggest that the hematopoietic specific proteins Grap2 and HPK1 form a signaling complex to mediate the c-Jun NH(2)-terminal kinase (JNK) signaling pathway in T cells.
 ...
PMID:Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. 1131 18

Hypertonicity-induced binding of the transcription factor TonEBP/OREBP to its cognate DNA element, ORE/TonE, is associated with increased transcription of several osmotically regulated genes. Previously, it was found that hypertonicity rapidly causes nuclear translocation and phosphorylation of TonEBP/OREBP and, more slowly, increases TonEBP/OREBP abundance. Also, the C terminus of TonEBP/OREBP was found to contain a transactivation domain (TAD). We have now tested for tonicity dependence of the TAD activity of the 983 C-terminal amino acids of TonEBP/OREBP. HepG2 cells were cotransfected with a reporter construct and one of several TAD expression vector constructs. The reporter construct contained GAL4 DNA binding elements, a minimal promoter, and the Photinus luciferase gene. TAD expression vectors generate chimeras comprised of the GAL4 DNA binding domain fused to (i) the 983 C-terminal amino acids of TonEBP/OREBP, (ii) 17 glutamine residues, (iii) the TAD of c-Jun, or (iv) no TAD. All TAD-containing chimeras were functional at normal extracellular osmolality (300 mosmol/kg), but the activity only of the chimera containing the 983 C-terminal amino acids of TonEBP/OREBP varied with extracellular NaCl concentration, decreasing by >80% at 200 mosmol/kg and increasing 8-fold at 500 mosmol/kg. The chimera containing the 983 C-terminal amino acids of TonEBP/OREBP was constitutively localized to the nucleus and showed tonicity-dependent posttranslational modification consistent with phosphorylation. The activity at 500 mosmol/kg was reduced by herbimycin, a tyrosine kinase inhibitor and by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, a protein kinase CK2 inhibitor. Thus, the 983 C-terminal amino acids of TonEBP/OREBP contain a TAD that is regulated osmotically, apparently by tonicity-dependent phosphorylation.
 ...
PMID:Activity of the TonEBP/OREBP transactivation domain varies directly with extracellular NaCl concentration. 1179 70

The effect of hyperosmolarity on CD95 membrane targeting and CD95 ligand (CD95L)-induced apoptosis was studied in rat hepatocytes. CD95 showed a predominant intracellular localization in normoosmotically exposed rat hepatocytes, whereas hyperosmotic exposure induced, within 1 hour, CD95 trafficking to the plasma membrane followed by activation of caspase-3 and -8. Hyperosmotic CD95 membrane targeting was sensitive to inhibition of c-Jun-N-terminal kinase (JNK), protein kinase C (PKC), and cyclic adenosine monophosphate, but not to inhibition of extracellular regulated kinases (Erks) or p38 mitogen activated protein kinase (p38(MAPK)). Hyperosmotic CD95 targeting to the plasma membrane was dose-dependently diminished by glutamine or taurine, probably caused by an augmentation of volume regulatory increase. Despite CD95 trafficking to the plasma membrane and caspase activation, hyperosmolarity per se did not induce apoptosis. Hyperosmolarity, however, sensitized hepatocytes toward CD95L-induced apoptosis, as assessed by annexin V staining and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling (TUNEL) assay. This sensitization was abolished when hyperosmotic CD95 membrane trafficking was prevented by cyclic adenosine monophosphate, PKC, or JNK inhibition, whereas these effectors had no effect on CD95L-induced apoptosis in normoosmotically exposed hepatocytes. CD95L addition under normoosmotic conditions caused CD95 membrane trafficking, which was sensitive to JNK inhibition, but not to cyclic adenosine monophosphate or inhibition of PKC, Erks, and p38(MAPK). In conclusion, multiple signaling pathways are involved in CD95 membrane trafficking. Hyperosmotic hepatocyte shrinkage induces CD95 trafficking to the plasma membrane, which involves JNK-, PKA-, and PKC-dependent mechanisms and sensitizes hepatocytes toward CD95L-mediated apoptosis.
 ...
PMID:Hyperosmolarity triggers CD95 membrane trafficking and sensitizes rat hepatocytes toward CD95L-induced apoptosis. 1219 52

Polyglutamine diseases, including Huntington's disease, designate a group of nine neurodegenerative disorders characterized by the presence of a toxic polyglutamine expansion in specific target proteins. Using cell and mouse models, we have shown that expanded polyglutamine led to activation of the stress kinase JNK and the transcription factor AP-1, which are implicated in neuronal death. Polyglutamine expansion-induced stress shared common features with protein-damaging stress such as heat shock, because activation of JNK involved inhibition of JNK phosphatase activities. Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6. Aggregation of M3/6 by polyglutamine expansion appeared to be indirect, because M3/6 was not recruited into polyglutamine inclusions. The heat shock protein HSP70, which is known to inhibit JNK during the heat shock response, suppressed polyglutamine-mediated aggregation of M3/6 and activation of JNK. Interestingly, levels of HSP70 were down-regulated by polyglutamine expansion. We suggest that reduction of HSP70 by expanded polyglutamine is implicated in aggregation and inhibition of M3/6 and in activation of JNK and AP-1.
 ...
PMID:Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. 1259 32

Mixed lineage kinases (MLKs) belong to the family of mitogen activated protein kinase kinase kinase (MAPKKK) and cause neuronal cell death mediated through c-Jun, N-terminal kinase (JNK) pathway. Recently, genetic studies in Drosophila revealed the presence of an MLK termed slipper (slpr). However, its biochemical features like physiological substrate, role in different MAPK pathways and developmental and tissue-specific expression pattern were not reported. Here, we report cDNA cloning, expression analysis and biochemical characterization of a Drosophila mixed lineage kinase (dMLK) that is also known as slipper. The protein structure analysis of dMLK/slipper revealed, in addition to the conserved domains, a stretch of glutamine in the amino terminus and an asparagine-threonine stretch at the carboxy-terminus. In situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that dMLK is expressed in early embryonic stages, adult brain and thorax. Ectopic expression of dMLK either in Drosophila S2 or in mammalian HEK293 cells leads to activation of JNK, p38 and extracellular signal regulated kinase (ERK) pathways. Further, dMLK directly phosphorylates Hep, dMKK4 and also their mammalian counterparts, MKK7 and SEK1, in an in vitro kinase assay. Taken together, our results provide for the first time a comprehensive expression profile and new biochemical insight of dMLK/slipper.
 ...
PMID:Drosophila mixed lineage kinase/slipper, a missing biochemical link in Drosophila JNK signaling. 1267 57

Huntington's disease (HD) is an autosomal neurodegenerative disorder, caused by expansion of a glutamine repeat in the Huntingtin protein. Pathogenesis in HD includes the cytoplasmic cleavage of Huntingtin and release of an amino-terminal fragment capable of nuclear localization, where expanded-Huntingtin (Exp-Htt) might lead to aberrant transcriptional regulation, neuronal dysfunction and degeneration. Recent evidence, from hippocampal cell lines, also implicates altered interaction of Exp-Htt with components of the c-Jun N-terminal kinase (JNK) cascade. However, there is yet no proven implication of the JNK/c-Jun module in degeneration of striatal neurons, the more vulnerable cell population, in HD. In the present study, we used primary striatal neurons in culture to analyze c-Jun activation by Exp-Htt. Green fluorescent protein (GFP)-tagged exon 1 of human Huntingtin either in its normal (25Q, normal-Htt) or expanded (103Q, Exp-Htt) version was transiently transfected in these cells. We first set out, in our conditions, the time course of striatal degeneration produced by Exp-Htt, and found it occurred rapidly. At 48 h post-transfection, 60% of striatal neurons expressing Exp-Htt had apoptotic characteristics including DNA fragmentation and neuritic retraction. Most of these neurons also showed nuclear aggregates of GFP-Exp Htt. Kinetics of c-Jun activation were tested in transfected cells using immunocytochemical detection of phospho-c-Jun. We found a significant activation and induction of c-Jun in Exp-Htt but not normal-Htt-transfected neurons. Of interest, these events occurred prior to nuclear translocation of Exp-Htt. Finally, overexpression of a dominant negative version of c-Jun, as well as pharmacological inhibition of JNK strongly protected against DNA fragmentation and neuritic retraction induced by Exp-Htt. Thus our data suggest that c-Jun activation and induction, is an early event in the pathogenesis of HD, occurring prior to formation of nuclear aggregates of Exp-Htt.
 ...
PMID:Expanded huntingtin activates the c-Jun terminal kinase/c-Jun pathway prior to aggregate formation in striatal neurons in culture. 1531 98

The mechanisms by which polyglutamine expansion causes common features of neuronal death remain unclear. Here we describe an approach for delivering polyglutamine expansions directly into cultured sympathetic neurons. Glutamine (Q) residues (n = 10, 22, 30) were conjugated with a peptide possessing translocation properties across plasma membranes (PDP) and a nuclear localization signal (NLS). These peptides were rapidly incorporated into sympathetic neurons and showed neurotoxicity in a length- and dose-dependent manner. A robust induction of c-jun and cyclin D1 occurred following treatment with PDP-Q22-NLS. Enhanced c-Jun phosphorylation showed c-Jun N-terminal kinase (JNK) activation. Coincidentally, TrkA tyrosine phosphorylation was decreased in association with loss of phospho-Akt, the downstream target of PI-3 kinase. Despite such proapoptotic signals, neither release of cytochrome c from mitochondria nor caspase-3/7 activation was detected. TdT-mediated dUTP nick-end labeling-positive nuclear condensation, but no fragmentation, occurred. At 24 hr of treatment, cytoplasmic Ca2+ levels began to become elevated, and the cellular level of ATP was decreased. Cytoplasmic Ca2+ responses to KCl depolarization displayed a delayed recovery, providing evidence for lack of Ca2+ homeostasis. The neurons became committed to death at about 36 hr when mitochondrial Ca2+ uptake declined concurrently with loss of mitochondrial membrane potential. Collectively, these results show that, despite induction of early apoptotic signals, nonapoptotic neuronal cell death occurred via perturbed Ca2+ homeostasis and suggest that mitochondrial permeability transition may play important roles in this model of neuronal death.
 ...
PMID:Early apoptotic and late necrotic components associated with altered Ca2+ homeostasis in a peptide-delivery model of polyglutamine-induced neuronal death. 1582 90

Huntington's disease (HD) is a neurodegenerative disorder resulting from the expansion of a glutamine repeat (polyQ) in the N-terminus of the huntingtin (htt) protein. Expression of polyQ-containing proteins has been previously shown to induce various cellular stress responses. Among these, activation of the c-Jun N-terminal kinase (JNK) cascade has been observed in cellular models of HD. However, the implication of the JNK pathway has not previously been evaluated in the striatum of HD animal models. Here we report that the JNK pathway participates in HD pathology in a rat model of the disease. Increased phosphorylation of the JNK target c-Jun was observed as early as 4 weeks and persisted for 13 weeks after lentiviral-mediated expression of htt171-82Q. In order to assess the importance of this pathway in HD pathology, JNK inhibitors including dominant-negative mutants of upstream kinases (ASK1(K709R), MEKK1(D1369A)), a c-Jun mutant (Delta169c-Jun) and the active domain of the scaffold protein JIP-1/IBI (IBI-JBD) were tested for their ability to mitigate the effect of htt171-82Q. The overexpression of MEKK1(D1369A) and JIP-1/IBI reduced the polyQ-related loss of DARPP-32 expression, while the other inhibitors had no effect. In all cases, the formation of EM48-positive htt inclusions and P-c-Jun immunoreactivity were unaltered. These results suggest that JNK activation is involved in HD and that blockade of this pathway may be of benefit in counteracting HD-related neurotoxicity.
 ...
PMID:Implication of the JNK pathway in a rat model of Huntington's disease. 1902 49

Sequence-specific DNA-binding activators, key regulators of gene expression, stimulate transcription in part by targeting the core promoter recognition TFIID complex and aiding in its recruitment to promoter DNA. Although it has been established that activators can interact with multiple components of TFIID, it is unknown whether common or distinct surfaces within TFIID are targeted by activators and what changes if any in the structure of TFIID may occur upon binding activators. As a first step toward structurally dissecting activator/TFIID interactions, we determined the three-dimensional structures of TFIID bound to three distinct activators (i.e., the tumor suppressor p53 protein, glutamine-rich Sp1 and the oncoprotein c-Jun) and compared their structures as determined by electron microscopy and single-particle reconstruction. By a combination of EM and biochemical mapping analysis, our results uncover distinct contact regions within TFIID bound by each activator. Unlike the coactivator CRSP/Mediator complex that undergoes drastic and global structural changes upon activator binding, instead, a rather confined set of local conserved structural changes were observed when each activator binds holo-TFIID. These results suggest that activator contact may induce unique structural features of TFIID, thus providing nanoscale information on activator-dependent TFIID assembly and transcription initiation.
 ...
PMID:Structures of three distinct activator-TFIID complexes. 1957 Nov 80

Cancer cells must avoid succumbing to a variety of noxious conditions within their surroundings. Acidosis is one such prominent feature of the tumor microenvironment that surprisingly promotes tumor survival and progression. We recently reported that acidosis prevents apoptosis of starved or stressed lymphoma cells through regulation of several Bcl-2 family members (Ryder et al., JBC, 2012). Mechanistic studies in that work focused on the acid-mediated upregulation of anti-apoptotic Bcl-2 and Bcl-xL, while additionally showing inhibition of glutamine starvation-induced expression of pro-apoptotic PUMA by acidosis. Herein we report that amino acid (AA) starvation elevates PUMA, an effect that is blocked by extracellular acidity. Knockdown studies confirm that PUMA induction during AA starvation requires expression of both CHOP and c-Jun. Interestingly, acidosis strongly attenuates AA starvation-mediated c-Jun expression, which correlates with PUMA repression. As c-Jun exerts a tumor suppressive function in this and other contexts, its inhibition by acidosis has broader implications for survival of cancer cells in the acidic tumor milieu.
 ...
PMID:Acidosis blocks CCAAT/enhancer-binding protein homologous protein (CHOP)- and c-Jun-mediated induction of p53-upregulated mediator of apoptosis (PUMA) during amino acid starvation. 2326 51


<< Previous 1 2 3 Next >>