Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 h, and then decreased with time. Angiotensin II synthesis increased at 45 min and 1 h, resulting in p38 mitogen-activated protein (MAP) kinase-driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 h to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH(2)-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT(1) and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT(1) blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.
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PMID:Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. 1157 21

Angiotensin II (Ang II) acts as a neuromodulator/neurotransmitter in specific brain nuclei involved in the regulation of blood pressure and volume homeostasis. It also induces a highly differentiated transcription factor expression in these nuclei. We investigated whether adrenoceptors, which modulate other central actions of angiotensin II like the vasopressin release, also play a role in the AT1 receptor-mediated expression of the transcription factors (TF) c-Fos, c-Jun and Krox-24 in the rat brain. Ang II, injected intracerebroventricularly, induced the expression of c-Fos, c-Jun and Krox-24 in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Pretreatment with the alpha 1-adrenoceptor antagonist, prazosin, significantly inhibited the Ang II-induced transcription factor expression in the SON and PVN. The alpha 2-adrenoceptor antagonist, yohimbine, also reduced Ang II-stimulated transcription factors significantly in both nuclei. This inhibition was mainly localized in vasopressinergic magnocellular neurons in both nuclei. The beta-adrenoceptor antagonist, propranolol, did not influence the Ang II-induced expression of TF. Our results show that both, Ang II-induced vasopressin release and transcription factor expression, involve the same neuronal connections in the brain, implicating that the signal transduction pathways leading to the two different effects are at least to a certain degree convergent.
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PMID:Involvement of adrenoceptors in the angiotensin II-induced expression of inducible transcription factors in the rat forebrain and hypothalamus. 1180 25

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.
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PMID:Integrins play a critical role in mechanical stress-induced p38 MAPK activation. 1184 90

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

Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogenactivated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta MHC), skeletal alpha-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2 alpha (SERCA2 alpha), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, PI3K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.
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PMID:Molecular mechanisms of cardiac hypertrophy induced by toxicants. 1221 66

Mitogen-activated protein kinases (MAP kinases), including extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38, play a central role in cellular responses by various stress stimuli such as cell proliferation, apoptosis, migration, or gene expression. Furthermore, activator protein-1 (AP-1), a transcription factor which can be activated by MAP kinases, also is involved in a variety of celllar responses, as well as MAP kinases. MAP kinases and AP-1 are significantly activated in vascular tissues by hypertension, angiotensin II, or balloon injury. We have made dominant negative mutants of MAP kinases or c-Jun, to specifically inhibit in vivo activation of MAP kinases or AP-1. Vascular gene transfer of each dominant negative mutant of MAP kinases or c-Jun prevents intimal hyperplasia after balloon injury, which is associated with the inhibition of smooth muscle cell proliferation in the intima and the media and probably also associated with inhibition of smooth muscle cell migration. However, in vitro findings on cultured vascular smooth muscle cells suggest that the molecular mechanism underlying inhibition of intimal hyperplasia may be different among each dominant negative mutant of MAP kinases and c-Jun. MAP kinases and c-Jun seem to be the promising therapeutic target for vascular remodeling.
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PMID:Stress and vascular responses: mitogen-activated protein kinases and activator protein-1 as promising therapeutic targets of vascular remodeling. 1268 38

Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Cardiomyocyte hypertrophy is characterized by increased cell size and altered gene expression. By differential-display polymerase chain reaction and Western blotting we found that the transcriptional coactivator MBF1 was upregulated during hypertrophy in cardiomyocyte cultures. Furthermore, MBF1 protein level increased in two animal models of hypertrophy, angiotensin II treatment and aortic banding. MBF1 antisense oligodeoxynuclotides blocked phenylephrine-induced hypertrophy, suggesting MBF1 plays a key role in hypertrophic growth. In contrast, overexpression of MBF1 potentiated the hormone-induced response of the atrial natriuretic peptide promoter. MBF1 overexpressed by transient transfection cooperated with the transcription factor c-Jun in activation of transcription but not with GATA4. MBF1 and c-Jun induced the activity of a transiently transfected atrial natriuretic peptide promoter, whereas neither MBF1 nor c-Jun could induce the promoter alone. Moreover, MBF1 bound to c-Jun in vitro. These data suggest that MBF1 is a transcriptional coactivator of c-Jun regulating hypertrophic gene expression. Inhibitor studies suggested that MBF1 activates the atrial natriuretic peptide promoter independently of the calcineurin and CaMK signaling pathways. Our results indicate that MBF1 participates in hormone-induced cardiomyocyte hypertrophy and activates hypertrophic gene expression as a coactivator of c-Jun.
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PMID:Multiprotein bridging factor 1 cooperates with c-Jun and is necessary for cardiac hypertrophy in vitro. 1272 99

This study characterizes 3 cases of mesenchymal chondrosarcoma (MC) utilizing a proteomic approach that allows for the detection, visual quantification, cellular compartmentalization, and assessment of the functional state of certain proteins that may promote tumor growth and/or oppose apoptosis. Immunohistochemical procedures were performed to detect the following protein antigens: CD99, interleukin (IL)-1alpha, IL-6, transforming growth factor (TGF)-alpha, conventional (c) protein kinase C (cPKC)-alpha, cPKC-betaII, phosphorylated (p)-PKC-alpha/betaII, c-kit (CD117), platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2/neu, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, p21ras, the alpha subunit of farnesyl and geranylgeranyl transferase (FTalpha/GGTalpha), phospho (p)-c-Jun N-terminal kinase (p-JNK), p-p38 mitogen-activated protein kinase (MAPK), cyclin D1, c-Jun, Ki-67, bcl-2, TGF-beta1 latency-associated peptide (LAP), TGF-betaRII, and cyclooxygenase (COX)-2. Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The results showed that malignant mesenchymal chondroblasts exhibit stronger expressions of CD99, IL-1alpha, cPKC-alpha, p-PKC-alpha/betaII, PDGFR-alpha, p-JNK, Ki-67, and bcl-2 antigens than their more mature-appearing chondrocytic counterparts in MC. In conclusion, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach characterized the mesenchymal chondroblasts as possessing pathways that incorporate PKC-alpha and PDGFR-alpha signaling and anti-apoptotic bcl-2 expression. Specific therapies to target the mesenchymal chondroblasts in mesenchymal chondrosarcoma might include interferon-alpha, rapamycin, ciprofloxacin, and STI571.
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PMID:Mesenchymal chondrosarcoma: molecular characterization by a proteomic approach, with morphogenic and therapeutic implications. 1281 16

Osteopontin (OPN), an RGD-containing extracellular matrix protein, is associated with arterial smooth muscle cell (SMC) activation in vitro and in vivo. Many cytokines and growth factors involved in vessel wall remodeling induce OPN overexpression. Moreover, we recently demonstrated that the extracellular nucleotide UTP also induces OPN expression and that OPN is essential for UTP-mediated SMC migration. Thus, we set out to investigate the mechanisms of OPN expression. The aim of this study was to identify transcription factors involved in the regulation of OPN expression in SMCs. First, we explored the contribution of mRNA stabilization and transcription in the increase of UTP-induced OPN mRNA levels. We show that UTP induced OPN mRNA increases via both OPN mRNA stabilization and OPN promoter activation. Then, to identify transcription factors involved in UTP-induced OPN transcription, we located a promoter element activated by UTP within the rat OPN promoter using a gene reporter assay strategy. The -96 to +1 region mediated UTP-induced OPN overexpression (+276+/-60%). Sequence analysis of this region revealed a potential site for AP-1 located at -76. When this AP-1 site was deleted, UTP-induced activation of the -96 to +1 region was totally inhibited. Thus, this AP-1 (-76) site is involved in UTP-induced OPN transcription. A supershift assay revealed that both c-Fos and c-Jun bind to this AP-1 site. Finally, we demonstrate that angiotensin II and platelet-derived growth factor, two main factors involved in vessel wall pathology, also modulated OPN expression via AP-1 activation.
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PMID:AP-1 is involved in UTP-induced osteopontin expression in arterial smooth muscle cells. 1297 Jan 13

Not all of the cardiovascular effects of angiotensin-converting enzyme (ACE) inhibitors can be attributed to changes in angiotensin II and bradykinin levels. Because the cytoplasmic tail of ACE is phosphorylated, we determined whether ACE inhibitors affect the phosphorylation of ACE and whether ACE possesses the characteristics of a signal transduction molecule. The ACE inhibitors ramiprilat and perindoprilat, and the substrate bradykinin (but not angiotensin I), enhanced the activity of ACE-associated CK2 and the phosphorylation of ACE Ser1270 in cultured endothelial cells. Mitogen-activated protein kinase kinase 7 and c-Jun N-terminal kinase (JNK) coprecipitated with ACE, and stimulation of endothelial cells with ACE inhibitors increased the activity of ACE-associated JNK and elicited the accumulation of phosphorylated c-Jun in the nucleus. Ramiprilat was however unable to activate JNK or to stimulate the nuclear accumulation of c-Jun in endothelial cells expressing a S1270A ACE mutant or in ACE-deficient cells. Because the ACE inhibitor-induced increase in ACE expression has been linked to the formation of c-Jun homodimers, we investigated whether ACE signaling via JNK contributes to this response in vitro and in vivo. Prolonged ramiprilat treatment increased ACE expression in primary cultures of human endothelial cells and in vivo (mouse lung), a response that was prevented by pretreatment with the JNK inhibitor SP600125. Thus, ACE is involved in outside-in signaling in endothelial cells and "ACE signaling" may be an important cellular mechanism contributing to the beneficial effects of ACE inhibitors.
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PMID:Angiotensin-converting enzyme is involved in outside-in signaling in endothelial cells. 1471 29


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