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)

Angiotensin II activates three major mitogen-activated protein kinases (MAPK) in vascular smooth muscle cells. Although other angiotensin II-induced MAPKs activation require transactivation of a growth factor receptor, the detailed mechanism by which angiotensin II activates c-Jun NH(2)-terminal kinase (JNK) remains unclear. Here, an immunosuppressant, cyclosporin A but not FK506, selectively inhibited angiotensin II-induced JNK activation in vascular smooth muscle cells. However, cyclosporin A had no inhibitory effect on angiotensin II-induced protein synthesis. Thus, angiotensin II-induced JNK activation but not protein synthesis is mediated by a mechanism sensitive to cyclosporin A, which is independent from calcineurin in vascular smooth muscle cells.
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PMID:Cyclosporin A inhibits angiotensin II-induced c-Jun NH(2)-terminal kinase activation but not protein synthesis in vascular smooth muscle cells. 1204 91

Angiotensin II (Ang II) exerts a potent growth stimulus on the heart and vascular wall. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) intracellular signaling pathway by Ang II mediates at least some of the mitogenic responses to this hormone. In other signaling systems that use the JAK/STAT pathway, proteins of the suppressor of cytokine signaling (SOCS) family participate in signal regulation. In the present study it is demonstrated that SOCS3 is constitutively expressed at a low level in rat heart and neonatal rat ventricular myocytes. Ang II at a physiological concentration enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors. After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway. Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide to SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-Jun expression after repetitive infusions of the hormone. Thus, SOCS3 is induced by Ang II in rat heart and neonatal rat ventricular myocytes and participates in the modulation of the signal generated by this hormone.
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PMID:Suppressor of cytokine signaling 3 is induced by angiotensin II in heart and isolated cardiomyocytes, and participates in desensitization. 1296 61

Angiotensin II (Ang II) acts via its type 1 (AT(1)) receptor in neurons to regulate the activity of multiple intracellular signaling molecules, including intracellular Ca(2+), protein kinase C, phosphatidylinositol 3-kinase (PI3-K), and c-Jun NH(2)-terminal kinase (JNK). The present studies investigated the upstream signaling molecules involved in the Ang II stimulation of activator protein-1 (AP-1) DNA binding in neurons. Treatment of neurons cultured from neonatal rat hypothalamus and brainstem with Ang II (100 nM) showed a time-dependent increase in AP-1 DNA binding and this effect was inhibited by the AT(1) receptor antagonist, losartan (1 microM), the PI3-K inhibitor, LY294002 (10 microM), and the JNK inhibitor, JNK inhibitor II (100 nM). Furthermore, Ang II (100 nM) causes a time-dependent increase in JNK activity which was attenuated by PI3-K inhibition. These data establish, for the first time, a signaling cascade involved in the Ang II activation of AP-1 DNA binding in neurons.
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PMID:Angiotensin II induction of AP-1 in neurons requires stimulation of PI3-K and JNK. 1452 34

The MEK1,2 (MAPK/ERK kinase 1 and 2) pathway mediates the up-regulation of plasminogen activator inhibitor-1 (PAI-1) expression in vascular smooth muscle cells by a variety of hormones, including angiotensin II. Transfection of constitutively active MEKK-1, an upstream activator of the mitogen-activated protein (MAP) kinase pathways, was used to isolate an enhancer element located between -89 and -50 bp in PAI-1 promoter that was activated by MEKK-1 and selectively blocked by the MEK1,2 inhibitor PD98059. Mutational analysis revealed that the MEKK-1 response element (MRE) contained 2 cis-acting Sp1- and AP-1-like sequences, located between -75 to -70 and -63 to -52 bp, respectively. Overexpression of Sp1 enhanced MEKK-1-induced MRE promoter activity and a dominant-negative c-Fos blocked this Sp1 response. The combination of Sp1 and c-Jun or c-Fos was required to activate this MRE. Angiotensin II (Ang II) stimulation increased c-Fos, c-Jun, and Sp1 binding to the MRE by 100-, 4.9-, and 1.9-fold, respectively, and these responses were inhibited by PD98059 and AT1 receptor antagonist candesartan. Intravenous Ang II infusion in rats increased aortic c-Fos binding to the MRE. This MRE sequence mediated a 4-fold increase of MEK1,2-dependent PAI-1/luciferase mRNA expression by angiotensin II stimulation. This report identifies the MEK1,2 response element that mediates angiotensin II-stimulated PAI-1 promoter activation and shows that activation of this element requires Sp1 and AP-1 co-activation.
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PMID:MEK1,2 response element mediates angiotensin II-stimulated plasminogen activator inhibitor-1 promoter activation. 1465 94

Angiotensin II is implicated in pathophysiological processes associated with vascular injury and repair, which include regulating the expression of numerous NF-kappaB-dependent genes. The present study examined the effect of angiotensin II on interleukin-1beta-induced NF-kappaB activation and the subsequent expression of inducible NO synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) in cultured rat vascular smooth muscle cells. Neither NF-kappaB activation nor iNOS or VCAM-1 expression was induced in cells treated with angiotensin II alone. However, when added together with interleukin-1beta, angiotensin II, through activation of the AT(1) receptor, inhibited iNOS expression and enhanced VCAM-1 expression induced by the cytokine. The inhibitory effect of angiotensin II on iNOS expression was associated with a down-regulation of the sustained activation of extracellular signal-regulated kinase (ERK) and NF-kappaB by interleukin-1beta, whereas the effect on VCAM-1 was independent of ERK activation. The effect of angiotensin II on iNOS was abolished by inhibition of p38 mitogen-activated protein kinase (MAPK) with SB203580, but not by inhibition of PI3 kinase with wortmannin or stress-activated protein kinase/c-Jun NH(2)-terminal kinase (JNK) with JNK inhibitor II. Thus, angiotensin II, by a mechanism that requires the participation of p38 MAPK, differentially regulates the expression of NF-kappaB-dependent genes in response to interleukin-1beta stimulation by controlling the duration of activation of ERK and NF-kappaB.
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PMID:Angiotensin II differentially regulates interleukin-1-beta-inducible NO synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) expression: role of p38 MAPK. 1500 68

The adaptor molecule Nck has been demonstrated to mediate Angiotensin II (AngII)-induced stimulation of p21-activated kinase (PAK) and c-Jun NH2-terminal kinase (JNK) in vascular smooth muscle cells (VSMC). We have previously demonstrated, that immunoprecipitation of Nck from VSMC stimulated by AngII yielded an unidentified 100 kD phosphotyrosine (pTyr) protein. The present study was aimed at identifying the Nck-associated 100 kD pTyr protein in VSMC. Several candidate proteins of appropriate size, that had been shown previously either to bind to Nck or had been implicated in signal transduction pathways leading to activation of PAK or JNK were tested for association with Nck in VSMC. The first candidate protein we tested was Git1, which did not bind to Nck in VSMC upon stimulation by AngII. However, we identified dynamin as a 100 kD protein that was bound to Nck in VSCM via interaction with the third Nck-SH3 domain. However, dynamin was not tyrosine phosphorylated by AngII treatment and seemed to be distinct from the 100 kD phosphotyrosine protein that was found in Nck immunoprecipitates. Future work will now have to identify the Nck-associated 100 kD pTyr protein and functional studies will have to address its role in AngII signaling.
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PMID:Identification of Nck interacting proteins in vascular smooth muscle cells. 1513 4

Angiotensin II (ANG II) has been shown to activate c-Jun NH2-terminal kinase (JNK) in cultured mesangial cells, but the functional implication of this phenomenon remains to be determined, largely due to the lack of an effective approach to block JNK. Therefore, the present study was carried out to examine whether JNK is involved in ANG II-induced cell proliferation in cultured human mesangial cells (HMCs) with the use of a newly developed JNK-selective blocker, SP-600125. Within minutes, treatment with 100 nM ANG II activated all three members of MAP kinase family, including extracellular signal-regulated protein kinase (Erk) 1/2, JNK, and p38 in cultured HMCs, as assessed by immunoblotting detection of phosphorylation of MAP kinases. ANG II-dependent activation of JNK was further confirmed by detection of increased phosphorylation and transcription activity of c-Jun after the ANG II treatment. SP-600125 ranging from 5 to 10 microM almost completely abolished the activation of JNK by ANG II without affecting the activities of Erk1/2 and p38. After treatment with 100 ng ANG II, there was a steady increase in [3H]thymidine incorporation that was blocked by SP-60025 in a dose- and time-dependent manner. Similarly, SP-600125 dose dependently reduced the ANG II-induced increase in cell number. The antiproliferative effect of SP-60025 was further determined by cell-cycle analysis with flow cytometry. Twenty-four hours after ANG II treatment, 50% of the quiescent HMCs (G0/G1) progressed into the S phase, and the cell cycle progression was almost completely prevented in the presence of SP-60025. Our data suggest that JNK mediates the proliferative effect of ANG II in cultured HMCs and thus represents a novel therapeutic target for treatment of chronic renal diseases.
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PMID:c-Jun NH2-terminal kinase mediation of angiotensin II-induced proliferation of human mesangial cells. 1570 17

Reactive oxygen species (ROS) participate in cardioprotection of ischemic reperfusion (I/R) injury via preconditioning mechanisms. Mitochondrial ROS have been shown to play a key role in this process. Angiotensin II (Ang II) exhibits pharmacological preconditioning; however, the involvement of NAD(P)H oxidase, known as an ROS-generating enzyme responsive to Ang II stimuli, in the preconditioning process remains unclear. We compared the effects of 5-hydroxydecanoate (5-HD; an inhibitor of mitochondrial ATP-sensitive potassium channels), apocynin (an NAD(P)H oxidase inhibitor), and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol; a membrane permeable radical scavenger) on pharmacological preconditioning by Ang II in rat cardiac I/R injury in vivo. Treatment with a pressor dose of Ang II before a 30-minute coronary occlusion reduced infarct size as determined 24 hours after reperfusion. The protective effects of Ang II were eliminated by pretreatment with 5-HD or apocynin, similar to tempol. Both 5-HD and apocynin suppressed the enhanced cardiac lipid peroxidation and activation of the apoptosis signal-regulating kinase/p38, c-Jun NH2-terminal kinase (JNK) pathways, but not the Raf/MEK/extracellular signal-regulated kinase pathway, elicited by acutely administered Ang II. Apocynin but not 5-HD suppressed Ang II-induced augmentations of the NAD(P)H oxidase complex formation (p47phox, p22phox, and Rac-1) and its activity in the heart. Finally, 5-HD suppressed superoxide production by isolated cardiac mitochondria without any effect on their respiration. These results suggest that the preconditioning effects of Ang II for cardiac I/R injury may be mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation.
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PMID:Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. 1583 27

Angiotensin II (Ang II) activates multiple signaling pathways leading to hyperplasia of cardiac fibroblasts. Reactive oxygen species (ROS) produced by Ang II stimulation are assumed to play pivotal roles in this process. Here, we show that ROS mediate Ang II-induced activation of nuclear factor of activated T cells (NFAT) in rat cardiac fibroblasts. Ang II-induced NFAT activation was suppressed by diphenyleneiodonium (an NADPH oxidase inhibitor), dominant negative (DN)-Rac, DN-p47(phox), and an inhibitor of Galpha(12/13) (Galpha(12/13)-specific regulator of G protein signaling domain of p115RhoGEF, p115-regulator of G protein signaling (RGS)). Stimulation of Ang II receptor increased the intracellular ROS level in a Rac- and p47(phox)-dependent manner. Because p115-RGS suppressed Ang II-induced Rac activation, Ang II receptor-coupled Galpha(12/13) mediated NFAT activation through ROS production by Rac activation. Ang II-induced nuclear translocation of the green fluorescent protein (GFP)-tagged amino-terminal region of NFAT4 (GFP-NFAT4) was suppressed by p115-RGS or BAPTA but not by diphenyleneiodonium. The expression of constitutively active (CA)-Galpha(12/13), CA-G translocation alpha(13), or CA-Rac increased the nuclear of GFP-NFAT4. These results suggest that NFAT activity is regulated by both Ca(2+)-dependent and ROS-dependent pathways. Furthermore, activation of c-Jun NH(2)-terminal kinase (JNK) induced by Ang II stimulation is required for NFAT activation because Ang II-induced NFAT activation was inhibited by SP600125, a selective JNK inhibitor. These results indicate that Ang II stimulates the nuclear translocation and activation of NFAT by integrated pathways including the activation of Galpha(12/13), Rac, NADPH oxidase, and JNK and that Galpha(12/13)-mediated ROS production is essential for NFAT transcriptional activation.
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PMID:Galpha12/13-mediated production of reactive oxygen species is critical for angiotensin receptor-induced NFAT activation in cardiac fibroblasts. 1582 47

Angiotensin II type 2 (AT2R) or bradykinin B2 (B2R) receptor activation enhances NO production. Recently, we demonstrated enhancement of NO production when AT2R and B2R are simultaneously activated in vivo. However, the mechanism involved in this enhancement is unknown. Using confocal fluorescence resonance energy transfer microscopy, we report the distance between the AT2R and B2R in PC12W cell membranes to be 50+/-5 A, providing evidence and quantification of receptor heterodimerization as the mechanism for enhancing NO production. The rate of AT2R-B2R heterodimer formation is largely a function of the degree of AT2R-B2R expression. The physical association between the dimerized receptors initiates changes in intracellular phosphoprotein signaling activities leading to phosphorylation of c-Jun terminal kinase, phosphotyrosine phosphatase, inhibitory protein kappaBalpha, and activating transcription factor 2; dephosphorylation of p38 and p42/44 mitogen-activated protein kinase and signal transducer inhibitor of transcription 3; and enhancing production of NO and cGMP. Controlling the expression of AT2R-B2R, consequently influencing their biologically active dimerization, presents a potential therapeutic target for the treatment of hypertension and other cardiovascular and renal disorders.
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PMID:Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization. 1675 89


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