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)

Chromogranin A (CgA) expression is specific to cells of endocrine and neuroendocrine (NE) tissues. Our transfection studies with CgA have identified two DNA regions 5' of the transcription start site that regulate CgA gene transcription: a distal regulatory region (DRR) located between -726 and -455, and a proximal regulatory region (PRR) between -60 and -26. In studies of the DRR using four human NE and six human non-NE cell lines, we demonstrated enhanced transcription of DRR-containing CgA-GH plasmids by the NE cells as a group compared to the non-NE cells. DNase I footprinting identified a protected area in the DRR from -570 to -555 base pairs (bp) composed of the sequence TAATGATGACTAAACA. Centered in this sequence is the simian virus 40 version of the activator protein-1-binding site, TGACTAA. Electrophoretic mobility shift assays (EMSAs) with an oligonucleotide containing the 27 bp of the DRR between -576 and -550, which we refer to as the distal regulatory element (DRE), produced a specific complex with the NE BEN and non-NE COS-1 cell nuclear extracts. The addition of c-Jun and c-Fos antibodies produced strong supershifts of the complex generated by COS-1 extract, but very weak supershifts of the complex formed by BEN extract. These EMSA studies suggest that NE cells such as BEN contain unique nuclear factors distinguishable from activator protein-1 that interact with the DRE. The enhancer effect of the 271-bp DRR could be replaced by the 27-bp DRE in both CgA and calcitonin promoter constructs in BEN cells. Replacement of the DRR with the DRE resulted in a further increase in expression from these plasmids, suggesting the presence of suppressor sequences in the DRR. In transfection studies of the PRR, deletion of its cAMP response element (CRE) dramatically lowered transcription. In addition to demonstrating that its CRE can bind CRE-binding protein, EMSAs with the PRR demonstrated that an intervening sequence between the CRE and the TATA box formed a complex with BEN cell nuclear extract. Our studies demonstrate that both the PRR and DRR are important for high level transcription of the CgA gene in NE cells. The presence of both distal and proximal 5'-regulatory regions in the human CgA gene indicates a complex mechanism of transcriptional regulation. Although the PRR is important for the formation of a functional transcription complex at the TATA region, the DRR is important for the enhancement of CgA gene expression in NE cells.
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PMID:Identification and characterization of a neuroendocrine-specific 5'-regulatory region of the human chromogranin A gene. 758 18

Peripheral axotomy of adult rat sensory neurons causes induction of the transcription factor c-Jun and increased expression of the neuropeptides vasoactive intestinal polypeptide (VIP), galanin and neuropeptide Y. To determine whether VIP induction is dependent on transcriptional regulation by c-Jun, we exploited the fact that c-Jun and VIP are also induced in cultured sensory neurons. We blocked c-Jun synthesis by microinjecting antisense oligonucleotides and found that VIP expression, determined by quantitative immunofluorescence, was specifically reduced. Blockade of c-June expression also resulted in reduced neuropeptide Y expression but left galanin, substance P and calcitonin gene-related peptide unaffected. Since in vitro electrophoretic mobility shift assays showed that a nominal cyclic AMP responsive element (CRE) associated with the rat VIP gene could bind c-Jun-containing transcription factor complexes, we next investigated whether VIP expression in sensory neurons might depend on transcription factor binding to the CRE. When a DNA plasmid containing multiple copies of the CRE was injected into newly cultured sensory neurons to sequester transcription factors binding the endogenous CRE, there was a selective reduction in VIP expression. VIP induction in sensory neurons therefore probably results from transcriptional activation by c-Jun acting in combination with other factor(s), possibly acting through the CRE. These results show that c-Jun can regulate transcription of other genes affected by axotomy and imply that it could be a key regulator of the neuronal axotomy response.
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PMID:Regulation of VIP and other neuropeptides by c-Jun in sensory neurons: implications for the neuropeptide response to axotomy. 899 97

Adult olivocerebellar axons are capable of vigorous regeneration when provided with growth-permissive environmental conditions. To elucidate the contribution of intrinsic properties to the regenerative capabilities of inferior olivary neurons, we have examined the cellular modifications occurring in these neurons following axotomy and target deprivation in the absence of exogenous growth-promoting influences. Axotomized inferior olivary neurons undergo perikaryal shrinkage, dendritic atrophy and a loss of anti-calbindin immunoreactivity. A conspicuous cell death occurs during the first few weeks after lesion, but about 35% of the affected neurons survive up to 60 days. Coincidentally, a subset of the injured nerve cells become strongly reactive for NADPH diaphorase histochemistry, and this expression is correlated with survival in the medial accessory olive and in the principal olive. In addition, the affected neurons express or maintain the expression of several markers related to regenerative processes, including transcription factors c-Jun, JunD and Krox-24, the growth-associated protein GAP-43 and the developmentally regulated calcitonin gene-related peptide (CGRP). The expression of all these markers is sustained up to two months after lesion, the longest survival time examined. These results show that although adult axotomized inferior olivary neurons undergo severe regressive modifications leading to a conspicuous cell loss, at least a subset of them is resistant to the lesion. In addition, the long-lasting expression of several axon-growth associated markers expressed in these neurons in response to injury reveals that they are endowed with a strong intrinsic regenerative potential.
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PMID:Degenerative phenomena and reactive modifications of the adult rat inferior olivary neurons following axotomy and disconnection from their targets. 962 55

We have investigated the mechanisms underlying regulation of the calcitonin gene-related peptide (CGRP) cell-specific enhancer. Recently, we reported that this enhancer is inhibited by serotonin type-1 (5-HT1) agonists, similar to currently used antimigraine drugs. We have now tested whether this repression involves a mitogen-activated protein (MAP) kinase pathway. We first demonstrate that the CGRP enhancer is strongly (10-fold) activated by a constitutively active MAP kinase kinase (MEK1), yielding reporter activities 100-fold above the enhancerless control. The involvement of a MAP kinase pathway was confirmed by down-regulation of reporter activity upon cotransfection of a dominant negative Ras. Activation of the enhancer by MEK1 was blocked in a dose-dependent manner by the 5-HT1 receptor agonist CGS 12066A (CGS). Since it is not known whether the CGRP enhancer factors are immediate targets of MAP kinases, we then used EIk-1- and c-Jun-dependent reporter genes that are directly activated by the ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinase) MAP kinases. CGS treatment repressed the activation of both of these reporters, suggesting that at least two MAP kinases are the immediate targets of CGS-mediated repression. We further demonstrate that 5-HT1 agonists inactivate ERK by dephosphorylation, even in the presence of constitutively activated MEK1. This inactivation appears to be due to a marked increase in the level of MAP kinase phosphatase-1. These results have defined a novel and general mechanism by which 5-HT1 receptor agonists can repress MAP kinase activation of target genes, such as CGRP.
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PMID:Serotonergic repression of mitogen-activated protein kinase control of the calcitonin gene-related peptide enhancer. 965 4

c-Fos, a component of the dimeric transcription factor AP-1, is necessary for osteoclast formation. To determine whether c-Fos can substitute for any or all of the stimuli needed for osteoclast induction, we infected osteoclast precursors with retroviral vectors expressing c-Fos or the Fos-related protein, Fra-1. The infected cells were incubated with or without osteoclast-inductive stimuli. Osteoclast formation from retroviral-infected precursors remained completely dependent on osteoclast-inductive stromal cells. Unexpectedly, infection of bipotential osteoclast-macrophage precursor cell lines with retroviruses expressing Fra-1 but not c-Fos caused a 10-100-fold increase in the number of precursors that developed calcitonin receptors associated with an increase in bone resorption. These observations suggest that, in the precursor cell lines, Fra-1 is a limiting factor for full responsiveness to the osteoclast-inductive environment. Fra-1 is therefore likely to play a role in osteoclast differentiation which is distinct from that of c-Fos.
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PMID:Fra-1 potentiates osteoclastic differentiation in osteoclast-macrophage precursor cell lines. 1019 56

To assess whether diabetes alters the content and/or expression of neuroactive agents and protooncogenes in afferent neurons of the vagus nerve, the nodose ganglia of streptozotocin (STZ)-induced diabetic rats were studied at 8, 16, and 24 weeks after induction of diabetes. Neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), the immediate early gene c-Jun, vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP) content and expression were measured in nodose ganglia of control, diabetic, and diabetic+insulin-treated rats using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The numbers of nNOS-immunoreactive (ir) neurons were increased in the nodose ganglion of diabetic compared to control rats at the 8- and 16-week time points. However, no change was noted in the nNOS mRNA content of the diabetic nodose ganglion at either time point. Moreover, no alterations in the numbers of vagal efferent NOS-containing neurons (labeled with NADPH-diaphorase histochemistry) were noted in the dorsal motor nucleus of the vagus (DMV) or the nucleus ambiguous (NA) of control, diabetic, and diabetic+insulin-treated rats at any time point. Neither the numbers of TH-ir neurons nor the content of TH mRNA was altered in the diabetic rats at the 8- and 16-week time points. However, 24 weeks of diabetes resulted in a reduction in the numbers of TH-ir neurons in the diabetic nodose ganglia when compared to control, an effect not seen in diabetic rats receiving insulin. The number of nodose ganglion neurons labeled for the protooncogene, c-Jun, was small yet slightly increased in the diabetic nodose ganglia at the 8-week time point and was reversed with insulin treatment. The increase in c-Jun-ir neurons was not found at 16 or 24 weeks of diabetes. VIP-ir and CGRP-ir were unchanged at any of the time points. These data show that diabetes affects the content of some, but not all, neuroactive agents in the nodose ganglion and may reflect a modest level of diabetes-induced damage and/or alterations in axonal transport in the vagus nerve.
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PMID:Streptozotocin-induced diabetes and the neurochemistry of vagal afferent neurons. 1203 29

Recent adrenomedullin (AM) gene-targeting studies have proposed a novel concept that AM plays a protective role against oxidative stress in vivo. The present study was undertaken to explore the underlying molecular mechanism of the putative antioxidant action of AM against angiotensin II (Ang II)induced reactive oxygen species (ROS) generation in rat vascular smooth muscle cells (VSMCs). Intracellular ROS levels were measured by dichlorofluoroscein fluorescence. Redox-sensitive c-Jun amino-terminal kinase (JNK) and ERK1/2 activation and gene expression induced by Ang II in VSMCs were also studied. AM dose-relatedly (10(-8)-10(-7) m) inhibited intracellular ROS generation stimulated by Ang II (10(-7) m), as mimicked by dibutyl-cAMP, the effect of which was inhibited by the pretreatment with N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride, a protein kinase A inhibitor, and calcitonin gene-related peptide(8-37), an AM/calcitonin gene-related peptide receptor antagonist. Ang II induced JNK and ERK1/2 activation via a redox-sensitive manner, whereas AM inhibited JNK, but not ERK1/2, activation by Ang II. Furthermore, AM inhibited Ang II-induced redox-sensitive gene expression (plasminogen activator inhibitor-1 and monocyte chemoattractant protein-1) in the same manner as N-acetyl-l-cysteine, a potent antioxidant. AM also inhibited Ang II-induced up-regulation of Nox1, a critical membrane-bound component of reduced nicotinamide adenine dinucleotide phosphate oxidase in VSMCs, in the same degree as N-acetyl-l-cysteine. Our study demonstrates for the first time that AM directly inhibits intracellular ROS generation via an AM receptor-mediated and c-AMP-protein kinase A-dependent mechanism in VSMCs and that AM with its potent antioxidant action inhibits redox-sensitive JNK activation and gene expression induced by Ang II. These data suggest that AM plays a protective role as an endogenous antioxidant in Ang II-induced vascular injury.
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PMID:Antioxidant effect of adrenomedullin on angiotensin II-induced reactive oxygen species generation in vascular smooth muscle cells. 1507 Aug 51

We aimed to determine whether rat olivocochlear neurons survive axotomy inflicted through cochlear ablation, or if they degenerate. To estimate their intrinsic potential for axonal regeneration, we investigated the expression of the transcription factor c-Jun and the growth-associated protein-43 (GAP43). Axonal tracing studies based on application of Fast Blue into the cochlea and calcitonin gene-related peptide immunostaining revealed that many, but not all, lateral olivocochlear neurons in the ipsilateral lateral superior olive degenerated upon cochleotomy. A decrease of their number was noticed 2 weeks after the lesion, and 2 months postoperative the population was reduced to approximately one quarter (27-29%) of its original size. No further reduction took place at longer survival times up to 1 year. Most or all shell neurons and medial olivocochlear neurons survived axotomy. Following cochleotomy, 56-60% of the lateral olivocochlear neurons in the ipsilateral lateral superior olive were found to co-express c-Jun and GAP43. Only a small number of shell and medial olivocochlear neurons up-regulated c-Jun expression, and only a small number of shell neurons expressed GAP43. Up-regulation of c-Jun and GAP43 in lateral olivocochlear neurons upon axotomy suggests that they have an intrinsic potential to regenerate after axotomy, but cell counts based on the markers Fast Blue and calcitonin gene-related peptide indicate that this potential cannot be exploited and degeneration is induced instead. The survival of one quarter of the axotomized lateral olivocochlear neurons and of all, or almost all, shell and medial olivocochlear neurons appeared to depend on connections of these cells to other regions than the cochlea by means of axon collaterals, which remained intact after cochleotomy.
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PMID:Cell death or survival: molecular and connectional conditions for olivocochlear neurons after axotomy. 1596 1

The present study evaluated some of the mechanisms underlying prostaglandin E2 (PGE2)-induced paw edema formation in mice. Intraplantar (i.pl.) injection of PGE2 (0.10-10.0 nmol/paw) into the hindpaw elicited a dose-related edema formation, with a mean ED50 value of 0.42 nmol/paw. The coinjection of selective E-prostanoid (EP)3 [(2E)-N-[(5-bromo-2-methoxyphenyl)-sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide; L826266), but not EP2 or EP4 (all 10 nmol/paw), receptor antagonists significantly inhibited PGE2-induced paw edema. Like L826266, the PGE2-induced paw edema was markedly reduced by treatment with pertussis toxin and phospholipase C (PLC) inhibitor 1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122). Likewise, the selective neurokinin (NK)1 receptor antagonist N-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-prolyl]-N-methyl-N-phenyl-methyl-3-(2-aphthyl)-l-alaninamide (FK888) and the antagonist of vanilloid receptor (TRPV1) receptors 4'-chloro-3-methoxycinnamanilide (SB366791) (both 1 nmol/paw) also significantly inhibited PGE2-mediated paw edema. Conversely, the selective NK2, NK3, and calcitonin gene-related peptide (CGRP) CGRP(8-37) receptor antagonists all failed to interfere with PGE2-induced paw edema. The neonatal treatment of mice with capsaicin was also able to reduce PGE2-induced paw edema. The inhibitors of protein kinase C (PKC) 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X) and mitogen protein-activated kinases (MAPKs; 30 nmol/paw) c-Jun NH2-terminal kinase (JNK) (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125), extracellular signal-regulated kinase (PD98059), and p38 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SB203580], but not protein kinase A, markedly decreased the PGE2-mediated edema formation. The i.pl. injection of PGE2 (3 nmol/paw) induced a significant activation of MAPKs, namely, JNK and p38, an effect that was largely prevented by the selective EP3 receptor antagonist L826266 (10 nmol/paw). Collectively, these findings indicate that edematogenic responses elicited by PGE2 are mediated by EP3 receptor activation, also involving the stimulation of PLC, PKC, and MAPKs pathways and the participation of TRPV1 and NK1 receptors. These results make a considerable contribution to our comprehension of the mechanisms involved in PGE2-mediated inflammatory responses in mice.
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PMID:Pharmacological and molecular characterization of the mechanisms involved in prostaglandin E2-induced mouse paw edema. 1664 3

In a previous study, we found that calcitonin gene-related peptide (CGRP) could be induced by proinflammatory factor IL-1beta in A549 human type II alveolar (AEII) epithelial cells. We investigated the mechanism of IL-1beta-induced CGRP secretion and found that the PKC-p38 MAPK-NF-kappaB pathway was involved. In the present study, we found that IL-1beta stimulation induced c-Jun N-terminal kinase (JNK) activity within 15min in A549 cells. In investigating whether JNK was involved in IL-1beta-induced CGRP secretion, the JNK II inhibitor SP600125 was used and it significantly attenuated IL-1beta-induced CGRP secretion and c-Jun activity, which was elevated after IL-1beta stimulation from mRNA to protein level. EMSA results showed the activation of activator protein 1 (AP-1) after 2-h IL-1beta stimulation, and the JNK II inhibitor blocked c-Jun and AP-1 activity. Bioinformatic analysis showed five predicted AP-1 binding sites on the promoter of beta-CGRP; deletion analysis identified an AP-1 consensus site at -643bp relative to the initiation site, which mediates the beta-CGRP gene transcription in response to IL-1beta. These data suggest that besides the PKC-p38 MAPK-NF-kappaB pathway, the JNK-AP-1 pathway is involved in IL-1beta-induced CGRP secretion in A549 human type II alveolar epithelial cells, and a 643-bp site upstream of the transcription start site on the promoter of beta-CGRP is the AP-1 response element.
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PMID:JNK-AP-1 pathway involved in interleukin-1beta-induced calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. 1748 80


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