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)

The neuropathology of Parkinson's disease is reflected in experimental animals treated with the selective nigrostriatal dopaminergic neurotoxin MPTP. Neurons exposed to MPTP (MPP(+)) express morphological features of apoptosis, although the intracellular pathways that produce this morphology have not been established. The c-Jun NH(2)-terminal kinase (JNK) signaling cascade has been implicated as a mediator of MPTP-induced apoptotic neuronal death based on the ability of CEP-1347/KT-7515, an inhibitor of JNK activation, to attenuate MPTP-induced nigrostriatal dopaminergic degeneration. In these studies, MPTP-mediated activation of the JNK signaling pathway was assessed in the nigrostriatal system of MPTP-treated mice. MPTP elevated levels of phosphorylated JNK and JNK kinase (MKK4; also known as SEK1 or JNKK), by 2.5- and fivefold, respectively. Peak elevations occurred soon after administration of MPTP and coincided with peak CNS levels of MPP(+). Increased MKK4 phosphorylation, but not JNK phosphorylation, was found in the striatum, suggesting that activation of MKK4 occurs in injured dopaminergic terminals. Both JNK and MKK4 phosphorylations were attenuated by pretreatment with l-deprenyl, indicating that these phosphorylation events were mediated by MPP(+). Moreover, CEP-1347/KT-7515 inhibited MPTP-mediated MKK4 and JNK signaling at a dose that attenuates MPTP-induced dopaminergic loss. These data implicate this signaling pathway in MPTP-mediated nigrostriatal dopaminergic death and suggest that it may be activated in the degenerative process in Parkinson's disease.
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PMID:MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. 1093 3

Increasing evidence suggests that apoptosis may be the underlying cell death mechanism in the selective loss of dopaminergic neurons in Parkinson's disease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP(+)) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP(+) led to the sequential phosphorylation and activation of JNK kinase (MKK4), JNK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the JNK binding domain of JNK-interacting protein-1 (a scaffold protein and inhibitor of JNK) inhibited this cascade downstream of MKK4 phosphorylation, blocked JNK, c-Jun, and caspase activation, the death of dopaminergic neurons, and the loss of catecholamines in the striatum. Furthermore, the gene transfer resulted in behavioral benefit. Therefore, inhibition of the JNK pathway offers a new treatment strategy for Parkinson's disease that blocks the death signaling pathway upstream of the execution of apoptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases.
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PMID:Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease. 1150 16

The prevalence of Parkinson's disease is higher in males than in females. Although the reason for this gender difference is not clear, the level of female steroid hormones or their receptors may be involved in the pathogenesis. The estrogen receptor subtype expressed in the midbrain is limited to the novel beta subtype, whose role in the central nervous system has not been resolved. We demonstrated that ligand-activated estrogen receptor beta suppressed dopaminergic neuronal death in an in vitro Parkinson's disease model which uses 1-methyl-4-phenylpyridinium ions (MPP(+)). MPP(+) treatment caused the upregulation of c-Jun amino-terminal kinase (JNK) and dopaminergic neuronal death, the latter being blocked by curcumin, an inhibitor of the c-Jun/AP-1 cascade. 17alpha- and 17beta-estradiol both protected dopaminergic neurons from MPP(+)-induced neuronal death and this was blocked by a pure antagonist of the estrogen receptor, ICI 182,780, but not by an inhibitor of estrogen receptor dimerization, YP537. These data indicated that the neuroprotection provided by 17alpha-estradiol was via inhibitory transcriptional regulation at the activator protein-1 (AP-1) site mediated by estrogen receptor beta. Thus, 17alpha-estradiol is a suitable candidate for neuroprotective therapy of Parkinson's disease because it is associated with few undesirable feminizing effects.
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PMID:Estradiol protects dopaminergic neurons in a MPP+Parkinson's disease model. 1212 7

SH-SY5Y neuroblastoma cells exposed to the complex I inhibitor/parkinsonian neurotoxin methylpyridinium ion (MPP(+)) activate both survival and death-promoting signaling pathways and undergo MEK/ERK-dependent, phosphatidylinositol-3 kinase-dependent, and c-Jun kinase-dependent cell death. Because genomic responses to MPP(+) are not extensively characterized, we used nylon cDNA arrays to measure gene expression following exposure to an apoptosis-producing [MPP(+)]. Many changes occurred within 5 min, and all gene expression changes appeared before biochemical and morphological markers of apoptosis. The majority of gene expression changes in SY5Y were not found in rho(0) cells, indicating dependence of these changes on intact electron transport activity. rho(0) cells exposed to MPP(+) produced different expression profiles, indicating the potential for responses independent of complex I inhibition. MPP(+)-induced gene expression patterns in normal SY5Y cells were sensitive to inhibitors of MEK/ERK (UO 126) or phosphatidylinositol-3 kinase (LY 294002), demonstrating regulation of gene expression by these survival-promoting signaling pathways. The primary signaling molecules mediating these MPP(+)-induced gene expression changes are unknown but ultimately utilize MEK/ERK and phosphatidylinositol-3 kinase signaling. Genes suppressed by UO 126 or LY 294002 during MPP(+) exposure may mediate cell survival; those expressed in the presence of UO 126 or LY 294002 may mediate cell death in this in vitro model of Parkinson's disease.
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PMID:Dependence on electron transport chain function and intracellular signaling of genomic responses in SH-SY5Y cells to the mitochondrial neurotoxin MPP(+). 1271 Sep 31

Sensitive to apoptosis gene (SAG), a novel zinc RING finger protein, exhibits anti-apoptotic and antioxidant activity against a variety of redox reagents. In the present study, we have determined that SAG suppresses 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neurotoxicity via the downregulation of ROS generation and c-Jun N-terminal kinase 1 (JNK1) activity. Both transient and constitutively overexpressed SAG were found to inhibit the MPP(+)-induced neurotoxicity of SH-SY5Y neuroblastoma cells. In the SAG-expressing cells, MPP(+) induced ROS generation was suppressed to a significant degree as compared to the cells treated only with MPP(+). MPP(+)-induced JNK1 activation was also determined to be suppressed markedly by SAG. Furthermore, SAG inhibits MEKK1 dependent c-Jun transcription activity in SH-SY5Y cells. Thus, we concluded that SAG is a cellular protective molecule, which appears to function as an antioxidant, suppressing MPP(+)-induced neurotoxicity.
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PMID:SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling. 1724 May 29

Inhibition of astrocytic apoptosis has been regarded as a novel prospective strategy for treating neurodegenerative disorders such as Parkinson's disease. In the present study, we demonstrated that iptakalim (IPT), an ATP-sensitive potassium channel (K(ATP) channel) opener, exerted protective effect on MPP(+)-induced astrocytic apoptosis, which was reversed by selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate. Further study revealed that IPT inhibited glutathione (GSH) depletion, mitochondrial membrane potential loss and subsequent release of pro-apoptotic factors (cytochrome c and apoptosis-inducing factor (AIF), and c-Jun NH(2)-terminal kinase/mitogen-activated protein kinases (MAPK) phosphorylation induced by MPP(+). Meanwhile, extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 inhibited the protective effect of IPT on MPP(+)-induced astrocytic apoptosis. Furthermore, IPT could also activate ERK/MAPK and maintain increased phospho-ERK1/2 level after MPP(+) exposure. Taken together, these findings reveal for the first time that IPT protects against MPP(+)-induced astrocytic apoptosis via inhibition of mitochondria apoptotic pathway and regulating the MAPK signal transduction pathways by opening mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in astrocytes. And targeting K(ATP) channels expressed in astrocytes may provide a novel therapeutic strategy for neurodegenerative disorders.
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PMID:ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. 1763 69

Neurodegenerative diseases such as Parkinson's disease are illnesses associated with high morbidity and mortality with few, or no effective, options available for their treatment. In addition, the direct cause of selective dopaminergic cell loss in Parkinson's disease has not been clearly understood. Taken together, several studies have demonstrated that melatonin has a neuroprotective effect both in vivo and in vitro. Accordingly, the effects of melatonin on 1-methyl, 4-phenyl, pyridinium ion (MPP(+))-treated cultured human neuroblastoma SK-N-SH cell lines were investigated in the present study. The results showed that MPP(+) significantly decreased cell viability. By contrast, an induction of phosphorylation of c-Jun, activation of caspase-3 enzyme activity, cleavage of DNA fragmentation factors 45 and DNA fragmentation were observed in MPP(+)-treated cells. These changes were diminished by melatonin. These results demonstrate the cellular mechanisms of neuronal cell degeneration induced via c-Jun-N-terminal kinases and caspase-dependent signaling, and the potential role of melatonin on protection of neuronal cell death induced by this neurotoxin.
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PMID:Melatonin inhibits MPP+-induced caspase-mediated death pathway and DNA fragmentation factor-45 cleavage in SK-N-SH cultured cells. 1764 89

Parkinson's disease (PD) is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Recent studies have described the activation of a stress-induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK-mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice. However, mice exhibit a strain-dependent susceptibility to MPTP. Identifying the point(s) of molecular divergence in the MPTP-induced response may provide insight into the cause of PD or a means to identify susceptibility to PD in humans. Here we examined JNK signaling and COX-2 induction in two strains of mice, the MPTP-sensitive C57BL/6J and the MPTP-resistant Swiss Webster (SW). We show that C57BL/6J and SW strains differ in JNK and c-Jun activation in response to MPTP. In addition, the MPTP-induced COX-2 response occurs exclusively in C57BL/6J mice. Furthermore, strain-specific responses to MPTP are not due to differences in MPP(+) levels and are not secondary to cell death. These results provide evidence toward a mechanism of strain-dependent sensitivity to MPTP.
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PMID:Response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) differs in mouse strains and reveals a divergence in JNK signaling and COX-2 induction prior to loss of neurons in the substantia nigra pars compacta. 1788 23

Many studies showed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was widely used to produce Parkinson's disease (PD)-like models in animals can elicit apoptosis with increase of caspase activity via its neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)). Another pathway shown in MPTP-mediated nigrostriatal dopaminergic cell death involved the c-Jun-N-terminal kinases (JNKs) which are stress-activated protein kinases (SAPKs). Activation of the JNKs leads to the activation of transcription factors such as c-Jun that regulates its own expression. However, it is not known whether the activation of c-Jun is crucial in the stimulation of caspases leading to apoptosis observed in PD-like models. The aim of this study was to investigate the cellular expression and phosphorylation of c-Jun and the caspase-9 activity in rat injured with an intranigral injection of MPP(+). Furthermore, we determined the effects of a cell-permeable peptide TAT-JBD, inhibiting selectively JNKs, on apoptosis markers and on the expression of tyrosine hydroxylase (TH). Our results showed that MPP(+) induced not only an activation of c-Jun but also an early and robust stimulation of caspase-9 in midbrain of rats. Furthermore, a preliminary intravenous injection of TAT-JBD reduced the caspase-9 activation specifically induced by MPP(+) suggesting a control of the JNKs pathway on the intrinsic way of apoptosis in MPP(+)-toxicity. However, the inhibition of the JNK pathway did not prevent TH inhibition, DNA fragmentation and Bad expression in MPP(+)-lesioned substantia nigra of rats. Therefore, the possibility of intervention on the JNK pathway as a therapeutic strategy in Parkinson's disease is questionable.
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PMID:A cell-permeable peptide inhibitor TAT-JBD reduces the MPP+-induced caspase-9 activation but does not prevent the dopaminergic degeneration in substantia nigra of rats. 1803 21

Parkinson's disease is a progressive neurodegenerative disorder, associated with the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Recent studies have shown that c-Jun-N terminal kinase pathways might be involved in the oxidative stress-induced neuronal demise. In addition, there are several studies demonstrating that selegiline protects neural cell degeneration. In view of the above, the toxic effects of MPP(+) and the protective roles of selegiline were studied in cultures of human neuroblastoma (SK-N-SH) cell lines in the present study. MPP(+) significantly decreased cell viability but increased reactive oxygen species formation and lipid peroxidation, and the said effects were attenuated by selegiline. MPP(+) did not change the total levels of c-Jun but enhanced phosphorylation of c-Jun at Ser73 and cleavage of DNA fragmentation factor 45, which were diminished by selegiline. MPP(+)-treated SK-N-SH cells exhibited an irregularly shaped nuclear chromatin or DNA fragmentation, which was abolished by selegiline. These data suggest that c-Jun-N terminal kinase pathways are involved in oxidative stress-induced dopaminergic neuronal degeneration and pretreatment with selegiline affords neuroprotection by inhibiting these cell death-signaling pathways.
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PMID:1-Methyl-4-phenyl-pyridinium ion-induced oxidative stress, c-Jun phosphorylation and DNA fragmentation factor-45 cleavage in SK-N-SH cells are averted by selegiline. 1880 49


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