Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depolarization of cultured bovine adrenal chromaffin cells with KCl increased the activity of a proline-directed protein kinase that phosphorylates tyrosine hydroxylase. Characterization of the KCl-activated protein kinase activity revealed that it shared similar biochemical and chromatographic properties with the microtubule-associated protein-2 kinase/extracellularly regulated kinase (MAP/ERK) family of protein kinases. This protein kinase activity was found to elute from Mono Q, Superose, and phenyl-Sepharose columns under conditions described for MAP/ERK kinases, and active fractions were found to react with specific antibodies directed against ERKs. The KCl-activated protein kinase was found to phosphorylate the serine 31 site of endogenous bovine adrenal tyrosine hydroxylase. This phosphorylation resulted in an approximately 2-fold activation of tyrosine hydroxylase.
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PMID:Microtubule-associated protein kinase-2 phosphorylates and activates tyrosine hydroxylase following depolarization of bovine adrenal chromaffin cells. 798 31

Intact bovine adrenal medullary chromaffin cells were preincubated with 32PO4, and the multiple-site phosphorylation of tyrosine hydroxylase (TH) was studied. Up to eight 32P-labeled peptides were produced by tryptic hydrolysis of TH; however, all of the tryptic phosphopeptides were derived from four phosphorylation sites--Ser8, Ser19, Ser31 and Ser40. In situ regulation of 32P incorporation into the latter three sites was demonstrated with a diverse set of pharmacological agents. 32P incorporation into Ser19 was preferentially increased by brief exposures to depolarizing secretagogues. Longer treatments also increased Ser31 and Ser40 phosphorylation. Nicotine, muscarine and vasoactive intestinal polypeptide--reflecting cholinergic and non-cholinergic components of sympatho-adrenal transmission--each produced different patterns of multiple-site phosphorylation of TH. Nicotine, bradykinin and histamine increased 32P incorporation at each of the three sites whereas muscarine, angiotensin II, endothelin III, prostaglandin E1, GABA and ATP selectively increased Ser31 phosphorylation. Nerve growth factor did not influence TH phosphorylation in chromaffin cells from adult adrenal glands but selectively increased Ser31 phosphorylation in chromaffin cells isolated from calf adrenal glands. 32P incorporation into Ser40 was selectively increased by forskolin and other cAMP-acting agents whereas vasoactive intestinal polypeptide increased Ser31 and Ser40 phosphorylation. Thus, the phosphorylation of TH in bovine chromaffin cells appears to be regulated at three sites by three separate intracellular signaling pathways--Ser19 via Ca2+/calmodulin-dependent protein kinase II; Ser31 via ERK (MAP2 kinases); and Ser40 via cAMP-dependent protein kinase. These signaling pathways, as well as the extracellular signals that were effective in stimulating them, are similar to those previously described for TH in rat pheochromocytoma cells. However, several of the pharmacological agents produced different patterns of multiple-site TH phosphorylation in the bovine chromaffin cells. These differences between tissues could be accounted for by differences in the coupling/access between the extracellular signal transduction systems and the intracellular signaling pathways as opposed to differences in the intracellular signaling pathways per se.
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PMID:Multiple signaling pathways in bovine chromaffin cells regulate tyrosine hydroxylase phosphorylation at Ser19, Ser31, and Ser40. 809 28

We have previously reported that chronic elevation of insulin in the CNS of rats results in opposing changes of the mRNA expression for the norepinephrine transporter (NET; decreased) and the dopamine transporter (DAT; increased). In the present study we tested the hypothesis that a chronic depletion of insulin would result in opposite changes of NET and DAT mRNA expression, from those observed with chronic elevation of insulin. Rats were treated with streptozotocin to produce hypoinsulinemic diabetes. One week later, steady state levels of mRNA were measured by in situ hybridization for NET in the locus coeruleus (LC) and for DAT in the ventral tegmental area/substantia nigra compacta (VTA/SNc). The mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for NE and DA synthesis, was measured in these same brain regions. In the diabetic animals, NET mRNA was significantly elevated (159 +/- 22% of average control level) while DAT mRNA was non-significantly decreased (78 +/- 9% of average control level). Additionally, TH mRNA was significantly altered in both the LC (131 +/- 11% of average control level) and VTA/SNc (79 +/- 5% of average control level). We conclude that endogenous insulin is one physiological regulator of the synthesis and re-uptake of NE and DA in the CNS.
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PMID:Diabetes causes differential changes in CNS noradrenergic and dopaminergic neurons in the rat: a molecular study. 893 Mar 8

Hypothalamic norepinephrine (NE) plays an important role in the control of sexual behavior and in the secretion of gonadotropin. Our previous study showed that coitus induced simultaneous increases in hypothalamic NE and GnRH releases in female but not in male rabbits. To investigate the activities in noradrenergic neurons during the coitus-induced process of an LH surge, we measured tyrosine hydroxylase (TH, the rate-limiting enzyme in NE synthesis) and NE transporter (NET, a key protein for NE cellular reuptake) mRNA levels in locus coeruleus (LC) noradrenergic cells in female New Zealand White rabbits. Changes in LC-TH and LC-NET mRNA levels were also measured in males as controls. Female rabbits were killed before coitus and at 15, 30, 60, 120, and 240 min after coitus (n = 6-7/time point); males were killed before and at 30, 60, and 120 min after coitus (n = 3/time). Individual brainstems were sectioned, the LC neurons punched, and TH and NET mRNAs were quantified by ribonuclease protection assay (RPA). Rabbit-specific TH (330 bp) and NET (503 bp) cDNAs were used as probes in the RPA for gene-specific signals. A rabbit 'house-keeping' cDNA (cyclophilin, 158 bp) was also cloned and used as an internal marker for tissue RNA content. Trunk blood was collected to determine serum LH levels. In female rabbits, serum LH levels rose by 15 min after coitus, reached peak concentrations at 1-2 h, and declined thereafter. The time interval for changes in TH and NET mRNA levels in females was similar to that in serum LH levels. Both TH and NET mRNAs increased significantly by 15 min (73% and 85% respectively) and were elevated for 2 h (87% and 111% respectively). TH mRNA levels returned to basal levels by 4 h after coitus, whereas NET mRNA values were elevated throughout the 4 h of observation. In contrast, LH, TH and NET mRNA levels did not change after coitus in males. The enhanced gene expression of both TH and NET in the LC in females, in accord with our previous demonstration of increased hypothalamic NE release, suggests that regulation of NE synthesis and reuptake is an integral part of the coitus-induced NE/GnRH/LH surge process that includes the initiation, sustenance or recovery of the release and/or storage of these neurochemicals.
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PMID:Tyrosine hydroxylase and norepinephrine transporter mRNA levels increase in locus coeruleus after coitus in rabbits. 946 Jun 52

Gonadotropin-releasing hormone (GnRH) is a key hypothalamic peptide that controls the secretion of pituitary gonadotropins, particularly luteinizing hormone (LH), and hence gonadal function. Hypothalamic GnRH is released in a pulsatile manner. In the female, the pattern of GnRH pulses, i.e., pulse frequency and amplitude, varies during different reproductive stages and among different species. Several central and peripheral signals modulate GnRH neuronal activities. Some of these signals are stimulatory to GnRH release, e.g., norepinephrine (NE) and neuropeptide Y (NPY); some are inhibitory, e.g., beta-endorphin and interleukin-1; others are both stimulatory and inhibitory, e.g., estradiol-17 beta (E2). The neuronal structures and chemical interactions that result in pulsatile GnRH release remain unresolved. However, the core of the so-called 'GnRH pulse-generator' likely involves NE and NE transporter (NET, the protein for pre-synaptic re-uptake of NE). Both secretion and re-uptake of NE may determine hypothalamic NE availability. Many of the GnRH-stimulating and GnRH-inhibiting signals may influence the 'pulse-generator' by acting on GnRH neurons as second level signals. Hypothalamic GnRH is also released in a "surge" manner that is triggered either by increasing levels of circulating steroids (E2 and progesterone) during the preovulatory period in spontaneous-ovulating species, or by coitus in induced-ovulating animals. The sequential steps and mechanisms by which the GnRH surge occurs after E2 or coitus are not clear. However, it is unlikely that the E2 or coital stimuli act directly on GnRH neurons; E2 receptors have not been found in GnRH cells whereas coital signals must stop in the brainstem before they reach the hypothalamus. The brainstem may be an extra-hypothalamic site where both E2 and coital stimuli are transformed into GnRH-stimulating signals. One such signal may be NE whose brainstem cell bodies send terminals into the hypothalamus. Evidence from our laboratory suggests that a hypothalamic NE surge occurs at the time of the preovulatory GnRH surge in both the monkey and rabbit. Moreover, gene expression of both tyrosine hydroxylase (the rate-limiting enzyme for NE synthesis) and NET (the rate-limiting factor for synaptic NE transmission) in the brainstem increases after E2 in the monkey and after coitus in the rabbit. Other hypothalamic and/or brainstem signals, i.e., NPY, galanin, beta-endorphin, nitrous oxide and gamma aminobutyric acid, are likely involved in generating, maintaining and/or modulating the GnRH surge process. A better understanding of the up-stream GnRH-regulating signals will help improve treatments for many reproductive disorders associated with stress, obesity, infection and aging.
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PMID:Neuroendocrine signals in the regulation of gonadotropin-releasing hormone secretion. 955 Dec 47

We have shown previously that the synergistic interaction of acidic fibroblast growth factor (aFGF) and a coactivator (dopamine, protein kinase A, or protein kinase C activator) will induce the novel expression of tyrosine hydroxylase (TH) in neurons of the developing striatum. In this study we sought to determine whether, concomitant with TH expression, there were unique changes in transcription factors binding the AP-1 regulatory element on the TH gene. Indeed, we found a significant recruitment of proteins into TH-AP-1 complexes as well as a shift from low- to high-affinity binding. Supershift experiments further revealed dramatic changes in the proteins comprising the AP-1 complexes, including recruitment of the transcriptional activators c-Fos, a novel Fos protein, Fos-B, and Jun-D. Concomitantly, there was a decrease in repressor-type factors ATF-2 and CREM-1. aFGF appeared to play a central but insufficient role, requiring the further participation of at least one of the coactivating substances. Experiments examining the signal transduction pathway involved in mediating these nuclear events demonstrated that the presence of only an FGF (1, 2, 4, 9) competent to induce TH caused the phosphorylation of mitogen-activated protein kinase (MAPK). Moreover, the treatment of cells with MEK/ERK inhibitors (apigenin or PD98059) eliminated TH expression and the associated AP-1 changes, suggesting that MAPK was a critical mediator of these events. We conclude that, during transdifferentiation, signals may be transmitted via MAPK to the TH-AP-1 site to increase activators and reduce repressors, helping to shift the balance in favor of TH gene expression at this and possibly other important regulatory sites on the gene.
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PMID:Regulation of tyrosine hydroxylase gene expression during transdifferentiation of striatal neurons: changes in transcription factors binding the AP-1 site. 976 63

Organisms respond to hypoxia through detection of blood oxygen levels by sensors at peripheral chemoreceptors and by receptors in certain key cells of the body. The pathways over which peripheral chemoreceptor signals are transmitted to respiratory muscles are well established. However, the intracellular pathways that transmit hypoxic stimulus to gene activation are just being identified. Using anti-sense c-fos strategy, we have shown that c-fos is essential for the activation of activator protein-1 transcription factor complex (AP-1) and subsequent stimulation of downstream genes such as tyrosine hydroxylase (TH; Mishra et al. 1998). The purpose of the present study was to identify intracellular pathways that link hypoxia to activation of c-fos. The results of the present study show that hypoxia causes Ca2+ influx through L-type voltage gated Ca2+ channels and that hypoxia-induced c-fos gene expression is Ca2+/calmodulin dependent. We also demonstrate that hypoxia activates the extracellular-regulated kinase (ERK) and p38, but not JNK. Further, phosphorylation of ERK is essential for c-fos activation via SRE cis-element. Further characterization of nuclear signalling pathways provides evidence for the involvement of Src, a non receptor protein tyrosine kinase, and Ras, a small G protein, in the hypoxia-induced c-fos gene expression. These results suggest a possible role for non-receptor protein tyrosine kinases in propagating signals from G-protein coupled receptors to the activation of immediate early genes such as c-fos during hypoxia.
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PMID:Intracellular pathways linking hypoxia to activation of c-fos and AP-1. 1084 52

Reactive gliosis is the most prominent response to diverse forms of central nervous system (CNS) injury. The signaling events that mediate this characteristic response to neural injury are under intense investigation. Several studies have demonstrated the activation of phosphoproteins within the mitogen-activated protein kinase (MAPK) and Janus kinase (JAK) pathways following neural insult. These signaling pathways may be involved or responsible for the glial response following injury, by virtue of their ability to phosphorylate and dynamically regulate the activity of various transcription factors. This study sought to delineate, in vivo, the relative contribution of MAPK- and JAK-signaling components to reactive gliosis as measured by induction of glial-fibrillary acidic protein (GFAP), following chemical-induced neural damage. At time points (6, 24, and 48 h) following methamphetamine (METH, 10 mg/kg x 4, s.c.) administration, female C57BL/6J mice were sacrificed by focused microwave irradiation, a technique that preserves steady-state phosphorylation. Striatal (target) and nontarget (hippocampus) homogenates were assayed for METH-induced changes in markers of dopamine (DA) neuron integrity as well as differences in the levels of activated phosphoproteins. GFAP upregulation occurred as early as 6 h, reaching a threefold induction 48 h following METH exposure. Neurotoxicant-induced reductions in striatal levels of DA and tyrosine hydroxylase (TH) paralleled the temporal profile of GFAP induction. Blots of striatal homogenates, probed with phosphorylation-state specific antibodies, demonstrated significant changes in activated forms of extracellular-regulated kinase 1/2 (ERK 1/2), c-jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), MAPK/ERK kinase (MEK1/2), 70-kDa ribosomal S6 kinase (p70 S6), cAMP responsive element binding protein (CREB), and signal transducer and activator of transcription 3 (STAT3). MAPK-related phosphoproteins exhibited an activation profile that peaked at 6 h, remained significantly increased at 24, and fell to baseline levels 48 h following neurotoxicant treatment. The ribosomal S6 kinase was enhanced over 60% for all time points examined. Immunoreactivity profiles for the transcription factors CREB and STAT3 indicated maximal increases in phosphorylation occurring at 24 h, and measuring greater than 2- or 17-fold, respectively. Specific signaling events were found to occur with a time course suggestive of their involvement in the gliotic response. The toxicant-induced activation of these growth-associated signaling cascades suggests that these pathways could be obligatory for the triggering and/or persistence of reactive gliosis and may therefore serve as potential targets for modulation of glial response to neural damage.
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PMID:Protein phosphorylation cascades associated with methamphetamine-induced glial activation. 1108 25

The Ets family contains a growing number of transcriptional activators and inhibitors, which activity is regulated by phosphorylation and protein-protein interactions. Among these factors, Ets1, Erg1 and Fli1 are expressed in endothelial cells during angiogenesis in normal and pathological development. The expression of these transcription factors is regulated by angiogenic factors in cultured endothelial cells, as well as by various stresses occurring during angiogenesis. Transfection experiments and transgenic mice analysis revealed that Ets family members are involved in the transcriptional regulation of endothelial specific genes such as those encoding Tie1 and -2, VEGFR1 and -2 and VE-Cadherin. In vitro studies plead for a role of Ets family members in endothelial cell adhesion, spreading and motility. Gene inactivation experiments show that Ets1 is dispensable for embryonic development. The phenotype of knocked-out embryos indicates that Tel is required for maintenance of the developing vascular network in the yolk sac. Altogether, we suggest that Ets family members act both positively and negatively during the different steps of the angiogenic process. The regulation of the initiation of gene transcription arises from the combined activity of different transcriptional regulators. Therefore very few transcription factors are specific for a physiological process, or a given cell type. The transcriptional network that regulates blood vessel formation involves transcription factors which are expressed in a variety of situations. The Lung Kruppel Like Factor (LKLF) which is required for blood vessel stabilisation during murine development is also expressed in the primitive vertebrae and in the lung of the adult (C.T. Kuo, M.L. Veselits, K.P. Barton, M.M. Lu, C. Clendenin, J.M. Leiden, The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilisation during murine embryogenesis, Genes Dev. 11 (22) (1997) 2996-3006). Scl/Tal1 which is essential for angiogenic remodelling of the yolk sac capillary network (J.E. Visvader, Y. Fujiwara, S.H. Orkin, Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development, Genes Dev. 12 (4) (1998) 473-479), is involved in blood cell development and is also expressed in the developing brain. The EPAS transcription factor which was thought to be endothelial cell specific in the mouse embryo (H. Tian, S.L. McKnight, D.W. Russell, Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells, Genes Dev. 11 (1) (1997) 72-82) is also expressed in the liver, kidney and cells of the sympathetic nervous system of the chick embryo (J. Favier, H. Kempf, P. Corvol, J.M. Gasc, Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase, FEBS Lett. 462 (1-2) (1999) 19-24). Ets1, which expression was originally detected in lymphoid cells of adult tissues, has been the first transcription factor to be identified in endothelial cells during angiogenesis in the embryo (B. Vandenbunder, L. Pardanaud, T. Jaffredo, M.A. Mirabel, D. Stehelin, Complementary patterns of expression of c-etsl, c-myb and c-myc in the blood-forming system of the chick embryo, Development 107 (1989) 265-274 [5]) and in tumours (N. Wernert, M.B. Raes, P. Lassalle, M.P. Dehouck, B. Gosselin, B. Vandenbunder, D. Stehelin, The c-ets 1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularisation and other forms of angiogenesis in man, Am. J. Path. 140 (1992) 119-127 [6]). Since then, the Ets family has extended and this review will emphasise the relationships between these factors and angiogenesis.
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PMID:The Ets family contains transcriptional activators and repressors involved in angiogenesis. 1131 8

In the present study, we examined whether the bone morphogenetic proteins (BMPs), which are important in the developmental specification of transmitter type in certain classes of neurons, might also play a role in signaling the differentiation of a dopaminergic (DA) phenotype. We found that BMP-2, -4 and -6 were each capable of inducing, in a dose and time dependent manner, moderate levels of the DA enzyme tyrosine hydroxylase (TH) in cultured neurons from the mouse embryonic striatum. In contradistinction to other TH-inducing agents, BMPs initiated de novo TH expression without the required synergy of exogenous growth factors or co-activating substances and in neurons presumably aged (E16) beyond the critical period for induction. However, the appearance of TH in induced cells was short-lived (24 h) and could not be prolonged by repeated supplementation with the BMPs. Inhibitors of the mitogen-activated protein kinase (MAPK/ERK) signaling pathway, PD98059 and apigenin, did not prevent TH induction by BMP-4, as they did other TH inducing agents, indicating that the MAPK/ERK pathway does not mediate BMPs effects on TH expression. We conclude that BMP-2, -4 and -6 can be added to the expanding inventory of agents capable of inducing TH, making them potentially important in the specification of a DA phenotype in stem/precursor cells for the treatment of Parkinson's disease.
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PMID:Induction of a dopaminergic phenotype in cultured striatal neurons by bone morphogenetic proteins. 1155 97


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