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)

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of extracellular depositions of fibrillar beta-amyloid (A beta), which is derived from the alternative processing of beta-amyloid precursor protein (APP). Although APP is thought to function as a cell surface receptor, its mode of action still remains elusive. In this study, we found that the culture medium derived from cortical neurons treated with an anti-APP antibody triggers the death of naive neurons. Biochemical and immunocytochemical analyses revealed the presence, both in the conditioned medium and in neurons, of increased levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. Furthermore, the expression of these proinflammatory mediators occurred through a c-Jun N-terminal protein kinase/c-Jun-dependent mechanism. Taken together, our findings provide evidence for a novel mechanism whereby neuronal APP in its full-length configuration induces neuronal death. Such a mechanism might be relevant to neuroinflammatory processes as those observed in AD.
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PMID:Antibody-bound beta-amyloid precursor protein stimulates the production of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 by cortical neurons. 1583 68

Activating transcription factor 2 (ATF2) is a member of the activator protein-1 family of transcription factors, which includes c-Jun and c-Fos. ATF2 is highly expressed in the mammalian brain although little is known about its function in nerve cells. Knockout mouse studies show that this transcription factor plays a role in neuronal migration during development but over-expression of ATF2 in neuronal-like cell culture promotes nerve cell death. Using immunohistochemical techniques we demonstrate ATF2 expression in the normal human brain is neuronal, is found throughout the cerebral cortex and is particularly high in the granule cells of the hippocampus, in the brain stem, in the pigmented cells of the substantia nigra and locus coeruleus, and in the granule and molecular cell layers of the cerebellum. In contrast to normal cases, ATF2 expression is down-regulated in the hippocampus, substantia nigra pars compacta and caudate nucleus of the neurological diseases Alzheimer's, Parkinson's and Huntington's, respectively. Paradoxically, an increase in ATF2 expression was found in the subependymal layer of Huntington's disease cases, compared with normal brains; a region reported to contain increased numbers of proliferating progenitor cells in Huntington's disease. We propose ATF2 plays a role in neuronal viability in the normal brain, which is compromised in susceptible regions of neurological diseases leading to its down-regulation. In contrast, the increased expression of ATF2 in the subependymal layer of Huntington's disease suggests a role for ATF2 in some aspect of neurogenesis in the diseased brain.
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PMID:Activating transcription factor 2 expression in the adult human brain: association with both neurodegeneration and neurogenesis. 1587 7

Protein kinases are being increasingly targeted in the quest for new therapeutics, and the c-Jun N-terminal kinases (JNKs) are no exception. Protein-kinase inhibitors are generally small molecules that show competitive inhibition with respect to ATP. However, a peptide has been developed that is an ATP-noncompetitive inhibitor of JNK. This article describes the use of this peptide in an increasing number of animal models of disease, including diabetes, stroke, neurotrauma, hearing loss and Alzheimer's disease. The efficacy of this peptide shows that JNK inhibition is an effective strategy for the treatment of these diseases and opens the possibility for testing whether JNK inhibition will be beneficial in other diseases, such as atherosclerosis, arthritis and a range of neurodegenerative diseases.
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PMID:Therapeutic promise of JNK ATP-noncompetitive inhibitors. 1588 11

Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.
Curr Alzheimer Res 2005 Jan
PMID:Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. 1597 85

In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.
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PMID:Up-regulation of astrocyte cyclooxygenase-2, CCAAT/enhancer-binding protein-homology protein, glucose-related protein 78, eukaryotic initiation factor 2 alpha, and c-Jun N-terminal kinase by a neurovirulent murine retrovirus. 1603 95

The c-Jun N-terminal kinases (JNKs), which are essential regulators of physiological and pathological processes, are involved in several diseases including diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. Inhibition of JNKs suppresses pathological features of these diseases but the many physiological functions of these enzymes argue against the use of sustained, systemic, nonspecific inhibition in the treatment of these diseases. For example, deletion of the gene that encodes JNK1 prevents insulin resistance but disrupts neuronal cytoarchitecture and initiates the pathology of Alzheimer's disease. Thus, it is not sufficient to inhibit selectively either JNKs or individual isoforms of JNK. Instead, the aim is to inhibit the damaging actions of JNK. This can be achieved using peptides that selectively block molecular domains of individual JNK signaling complexes (exclusively) that form under pathological conditions. To date, peptide inhibitors of JNK have been successful in protecting against ischemia-induced brain damage and insulin resistance following obesity. In this review, we discuss novel pharmacological strategies to inhibit JNK and the limitations of these strategies.
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PMID:Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage. 1605 42

As aged population dramatically increases in these decades, efforts should be made on the intervention for curing age-associated neurodegenerative diseases such as Alzheimer's disease (AD). Natural plant extracts of Lycium barbarum are well-known to exhibit anti-aging effects. We therefore hypothesized that they exhibit neuroprotective effects against toxins in aging-related neurodegenerative diseases. In this study, we aimed to investigate whether extracts from L. barbarum have neuroprotective effects against toxicity of fibrillar Abeta(1-42) and Abeta(25-35) fragments. Primary rat cortical neurons exposed to Abeta peptides resulted in apoptosis and necrosis. Pre-treatment with extract isolated from L. barbarum significantly reduced the release of lactate dehydrogenase (LDH). In addition, it attenuated Abeta peptide-activated caspases-3-like activity. The extract elicited a typical dose-dependent neuroprotective effect. Effective dosage of this extract was wider than that of a well-known western neuroprotective medicine lithium chloride (LiCl). We have further examined the underlying mechanisms of the neuroprotective effects. In agreement with other laboratories, Abeta peptides induce a rapid activation of c-Jun N-terminal kinase (JNK) by phosphorylation. Pre-treatment of aqueous extract markedly reduced the phosphorylation of JNK-1 (Thr183/Tyr185) and its substrates c-Jun-I (Ser 73) and c-Jun-II (Ser 63). Taken together, we have proved our hypothesis by showing neuroprotective effects of the extract from L. barbarum. Study on anti-aging herbal medicine like L. barbarum may open a new therapeutic window for the prevention of AD.
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PMID:Neuroprotective effects of anti-aging oriental medicine Lycium barbarum against beta-amyloid peptide neurotoxicity. 1613 64

Obesity and insulin resistance are strongly associated with systemic markers of inflammation and endoplasmic reticulum stress. c-Jun N-terminal kinases (JNK) are activated by inflammatory cytokines and have a key role in beta-cell apoptosis and in negative regulation of insulin signaling. JNK1-deficient mice are protected from diet-induced obesity and insulin resistance, while genetically obese mice with targeted mutations in JNK1 are leaner and have reduced insulin and blood glucose levels. These studies validate JNK as a link between inflammation and metabolic diseases and as a promising drug target. This review highlights recent advances in small-molecule inhibitors of JNK that have also been targeted for other diseases with an inflammatory component such as stroke, rheumatoid arthritis, and Alzheimer's and Parkinson's diseases.
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PMID:JNK: bridging the insulin signaling and inflammatory pathway. 1625 18

Alzheimer's disease (AD) pathology is characterized by the presence of insoluble beta-amyoid deposits and neurofibrillary tangles containing hyperphosphorylated tau. Increased expression of the immediate early gene product c-Jun has also been reported in post-mortem AD brains, and the presence of upstream regulators of c-Jun has been described in tangle formations. Here, we report the presence of c-Jun specifically phosphorylated on ser-63, but not ser-73, in tangle-bearing neurons and in 'late-stage' extracellular tangles in AD brains. Western blot analysis confirmed the presence of c-Jun phosphorylated on ser-63 but not on ser-73 in AD brain tissue. The expression of differentially phosphorylated c-Jun in the AD brain may reflect the contradictory roles of these phosphorylation sites in neurons. Furthermore, the inappropriate sequestration of phosphorylated c-Jun in tangles in AD brains may contribute to AD pathology and neurodegeneration.
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PMID:Activated c-Jun is present in neurofibrillary tangles in Alzheimer's disease brains. 1648 Nov 6

Hyper-phosphorylated tau deposition in Pick bodies and neuron loss are major hallmarks of Pick's disease (PiD). However, there is no regional correlation between neuron loss and Pick bodies, as illustrated in dentate gyrus, where Pick bodies are present in almost every neuron, whereas cell death, if present, is not a major event. In order to better understand the possible role of selected transcription factors and members of the caspase family in cell death and cell survival, immunohistochemistry to c-Fos, c-Jun, CREB-1, ATF-2; c-Fos(P), c-Jun(P) and CREB-1(P); and procaspase-8, procaspase-3 and active (cleaved) caspase-3 immunohistochemistry was carried out in the frontal cortex and hippocampus. Increased expression of c-Fos, c-Jun, CREB-1 and ATF-2 was observed in PiD cases. Increased c-Fos(P), c-Jun(P) and CREB-1(P) was also found in the nuclei of neurons in diseased brains. Interestingly, c-Fos but not c-Fos(P) co-localized in many Pick bodies, as observed by double labelling-immunofluorescence and confocal microscopy. Pro-caspase-8 and pro-caspase-3 were increased in PiD. Moreover, granular active caspase-3 was observed in the nuclei as was aggregated active caspase-3 in the cytoplasm of neurons in PiD. Finally, double-labelling immunofluorescence and confocal microscopy disclosed co-localization of cytoplasmic active caspase-3 only in neurons with Pick bodies. Together, these findings show an increased expression of selected transcription factors and active (phosphorylated) forms in PiD, c-Fos sequestration in Pick bodies, and increased active caspase-3 expression in relation with Pick bodies. Since all these findings were observed equally in neurons of both vulnerable regions (frontal cortex) and resistant regions (dentate gyrus), it may be suggested that transcription factors are only barely related with cell death. Active caspase-3 is associated with tau deposition in Pick bodies, but it is not a marker of cell death in the dentate gyrus in PiD. The present findings are in line with the previous studies showing tau products cleaved by caspase-3, as recognized by specific tau-cleaved antibodies, in Alzheimer's disease and other tauopathies.
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PMID:Expression of transcription factors c-Fos, c-Jun, CREB-1 and ATF-2, and caspase-3 in relation with abnormal tau deposits in Pick's disease. 1649 65


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