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)

Three adrenergic receptor families that selectively activate three different G proteins (alpha1/Gq/11, alpha2/Gi, and beta/Gs) were used to study mitogen-activated protein kinase (MAPK) activation and differentiation in PC12 cells. PC12 cells were stably transfected with alpha1A-, alpha2A-, or beta1-adrenergic receptors (ARs) in an inducible expression vector, and subclones were characterized. Norepinephrine stimulated inositol phosphate formation in alpha1A-transfected cells, inhibited cyclic adenosine 3'5'-monophosphate (cAMP) formation in alpha2A-transfected cells, and stimulated cAMP formation in beta1-transfected cells. Nerve growth factor activated extracellular signal-regulated kinases (ERKs) in all cell lines; however, norepinephrine activated ERKs only in alpha1A- and beta1-transfected cells but not in alpha2A-transfected cells. Norepinephrine also activated c-Jun NH2-terminal kinase and p38 MAPK in alpha1A-transfected cells but not in beta1- or alpha2A-transfected cells. Norepinephrine caused differentiation of PC12 cells expressing alpha1A-ARs but not those expressing beta1- or alpha2A-ARs. However, norepinephrine acted synergistically with nerve growth factor in promoting differentiation of cells expressing beta1-ARs. Whereas ERKs are activated by Gi- but not Gs-linked receptors in many fibroblastic cell lines, we observed the opposite in PC12 cells. The results show that activation of the different G protein signaling pathways has different effects on MAPKs and differentiation in PC12 cells, with Gq signaling pathways activating all three major MAPK pathways.
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PMID:Differential coupling of alpha1-, alpha2-, and beta-adrenergic receptors to mitogen-activated protein kinase pathways and differentiation in transfected PC12 cells. 973 58

1. The effects of intraperitoneally (i.p.) administered noradrenaline and adrenaline on the hepatic expression of immediate early genes (IEGs) were studied in mice. 2. Intraperitoneal injections of various doses (0.2-2 mg kg(-1)) of noradrenaline and adrenaline dose-dependently induced hepatic c-fos and c-jun mRNA levels. The time-course study showed that there was an increase in c-fos and c-jun mRNA levels within 15 min, which reached a peak at 30 min, and returned to the basal levels 1-2 h after noradrenaline or adrenaline injection (2 mg kg(-1), i.p.). A Western blot assay revealed that c-Jun protein levels were maximally increased at 30 min and 1-2 h in noradrenaline- and adrenaline-treated mice, respectively. There was a slight increase in c-Fos protein, while 46-kDa Fra protein was prominently increased. Noradrenaline (2 mg kg(-1), i.p.) induced 46-kDa Fra within 15 min, which reached a maximum at 30 min and returned to the basal levels by 1 h. Adrenaline (2 mg kg(-1), i.p.) induced 46-kDa Fra at 30 min, which returned to the basal levels at 4 h. 3. Noradrenaline (2 mg kg(-1), i.p.)-induced increases in c-fos and c-jun mRNA expressions were inhibited by the pre-treatment with prazosin (alpha1-adrenergic antagonist; 0.5 mg kg(-1), i.p.), but not with yohimbine (alpha2-adrenoceptor antagonist; 1 mg kg(-1), i.p.) nor with propranolol (beta-adrenoceptor antagonist; 10 mg kg(-1), i.p.). Adrenaline (2 mg kg(-1), i.p.)-induced increases in c-fos and c-jun mRNA expressions were inhibited by the pre-treatment with prazosin or with propranolol, but not with yohimbine. Administration of ICI-118,551 (beta2-adrenoceptor antagonist; 2 mg kg(-1), i.p.), but not betaxolol (beta1-adrenoceptor antagonist; 2 mg kg(-1), i.p.), blocked adrenaline (2 mg kg(-1), i.p.)-induced increases in c-fos and c-jun mRNA expressions. 4. The results suggest that noradrenaline elicits the hepatic c-fos and c-jun mRNA responses by stimulating alpha1-adrenergic receptors, whereas in the case of adrenaline, this is elicited by stimulating both alpha1- and beta2-adrenergic receptors in mice. These catecholamine-induced hepatic IEG responses may be responsible for mediating some of the catecholamine actions in the liver.
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PMID:Differential effects of adrenaline and noradrenaline on the hepatic expression of immediate early genes in mice. 975 35

Coupling of the three known alpha1-adrenergic receptor (alpha1-AR) subtypes to mitogen-activated protein kinase (MAPK) pathways were studied in stably transfected PC12 cells. Subclones stably expressing alpha1A-, alpha1B-, and alpha1D-ARs under control of an inducible promoter, or at high and low receptor density, were isolated and characterized. Radioligand binding showed similar ranges of expression of each subtype. Norepinephrine (NE) increased inositol phosphate formation and intracellular Ca2+ level in these cells in a manner dependent on receptor density. However, alpha1A-ARs activated these second messenger responses more effectively than alpha1B-ARs, whereas alpha1D-ARs were least effective. NE stimulated activation of extracellular signal-regulated kinases (ERKs) in cells expressing all three alpha1-AR subtypes, although alpha1A- and alpha1B-ARs caused larger ERK activation than did alpha1D-ARs. Nerve growth factor (NGF) caused similar levels of ERK activation in all subclones. NE also activated p38 MAPK in alpha1A- and alpha1B- but not alpha1D-transfected cells and activated c-Jun NH2-terminal kinase (JNK) only in alpha1A-transfected cells. NE, but not NGF, strongly stimulated tyrosine phosphorylation of a 70-kDa protein only in alpha1A-transfected PC12 cells. NE caused neurite outgrowth only in alpha1A-expressing PC12 cells, but not in alpha1B- or alpha1D-transfected cells, whereas NGF caused neurite outgrowth in all cells. These studies show that alpha1A-ARs activate all three MAPK pathways, alpha1B-ARs activate ERKs and p38 but not JNKs, and alpha1D-ARs only activate ERKs. Only the alpha1A-AR-expressing cells differentiated in response to NE. The relationship of these responses to second messenger pathways activated by these subtypes is discussed.
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PMID:Differential activation of mitogen-activated protein kinase pathways in PC12 cells by closely related alpha1-adrenergic receptor subtypes. 1034 48

We examined the relative roles of the mitogen-activated protein kinases (MAPK) in mediating the alpha1-adrenergic receptor (alpha1-AR) stimulated hypertrophic phenotype in adult rat ventricular myocytes (ARVM). Norepinephrine (NE; 1 microM) in the presence of the beta -AR antagonist propranolol (Pro; 2 microM) caused activation of Ras (>six-fold), MAPK/ERK kinase 1 and 2 (MEK1/2, >10-fold) and extracellular signal-regulated kinases 1 and 2 (ERK1/2, approximately 30-fold) within 5 min, as determined by kinase activity assays and Western blots using phospho-specific antibodies. Conversely, p38 and c-Jun amino-terminal kinases (JNK) were not activated by NE/Pro. Activated MEK1/2 signals remained detectable at 2 h, and activated ERK1/2 remained detectable at 48 h. The alpha1-AR selective inhibitor prazosin (100 nM) completely inhibited the NE/Pro-stimulated activation of Ras, MEK1/2 and ERK1/2. The MEK inhibitor PD98059 caused a concentration-dependent inhibition of NE/Pro-stimulated protein synthesis (as assessed by [3H]leucine incorporation and cellular protein accumulation) and ERK1/2 activation, with approximately 50% inhibition at a concentration between 10 and 50 microM, which is consistent with the known IC50 values of PD98059 for MEK1 (4 microM) and MEK2 (50 microM). Thus, these data show that alpha1-AR stimulated hypertrophy in ARVM is dependent on the MEK1/2-ERK1/2 signaling pathway.
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PMID:MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. 1127 30

This study was undertaken to determine whether gene expression for transcriptional factors such as c-Fos and c-Jun is regulated by phospholipase C (PLC) activity. Norepinephrine (NE) increased PLC beta(1), beta(3), gamma(1), and delta(1) isozyme gene expression, protein contents and their activities in adult rat cardiomyocytes. Increases in PLC beta(1), beta(3), gamma(1), and delta(1) activities and gene expression in response to NE were prevented by prazosin, an alpha(1)-adrenoceptor (AR) antagonist. Furthermore, mRNA levels for c-Fos and c-Jun, unlike other transcriptional factors, were increased by both NE and phenylephrine, a specific alpha(1)-AR agonist. Increases in c-Fos and c-Jun gene expression due to NE were attenuated by both prazosin and a PLC inhibitor, U73122. Activation of protein kinase C (PKC) with phorbol myristate acetate increased c-Fos and c-Jun mRNA, whereas inhibition of PKC with bisindolylmaleimide as well as inhibition of extracellular signal-regulated kinases (ERK) 1/2 with PD98059 abolished the NE-induced increase in c-Fos and c-Jun gene expression. Reduction of c-Jun phosphorylation by SP600125, an inhibitor of JNK activity, was associated with an attenuation of the NE-induced increases in PLC gene expression. It is suggested that c-Fos and c-Jun gene expression is regulated by PLC in adult cardiomyocytes through a PKC- and ERK1/2-dependent pathway.
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PMID:Regulation of c-Fos and c-Jun gene expression by phospholipase C activity in adult cardiomyocytes. 1922 67

Norepinephrine (NE) and glucocorticoids (GCs) have been shown to oppositely affect various aspects of neuronal plasticity. These findings provided the basis for the plasticity hypothesis of major depression, which suggests that the disease-related impairment in neuronal plasticity is associated with long-term increase in GCs and may be reconstituted by antidepressants and monoamines. To investigate the interaction between GCs and NE, the plasticity-relevant ERK/MAPK pathway was studied in SH-SY5Y neuroblastoma cells treated with dexamethasone (DEX), a synthetic GC, NE, or both. NE treatment activated ERK and c-Jun and increased AP-1 transcriptional activity. Although DEX had no effect, co-treatment caused a prolonged and robust activation of the ERK/AP-1 pathway beyond NE-induced activation. Co-treatment also induced hyperactivation of CREB as compared to NE activation while DEX decreased pCREB. Independent alterations of ERK and CREB suggest an upstream point of interaction. Yohimbine, an alpha(2)-adrenergic receptor (AR) antagonist, prevented the hyperactivation of the ERK/AP-1 pathway and CREB induced by co-treatment. Immunofluorescence showed that after 2h of NE treatment, beta-arrestin was co-localized with the alpha(2)-AR at the plasma membrane while following co-treatment beta-arrestin was diffused within the cell, suggesting that DEX delays AR downregulation by altering beta-arrestin translocation. These results show a novel complex interaction by which GCs augment NE-induced intracellular signaling that may be relevant to antidepressant mode of action.
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PMID:Dexamethasone enhances the norepinephrine-induced ERK/MAPK intracellular pathway possibly via dysregulation of the alpha2-adrenergic receptor: implications for antidepressant drug mechanism of action. 2060 57