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)

The IL-6-related cytokines, LIF and cardiotrophin-1, are important growth promoting and cardioprotective agents for cardiomyocytes. However, factors that regulate their actions in the heart are poorly understood. In this study, we tested the hypothesis that endothelin-1, a peptide hormone that produces a pattern of cardiac hypertrophy distinct from LIF and cardiotrophin-1, modulates LIF-induced signaling in cardiomyocytes. Upon binding LIF or cardiotrophin-1, the LIF receptor alpha subunit (LIFRalpha) dimerizes with gp130, leading to activation of constitutively associated Jak1 proteins and LIFRalpha-gp130 tyrosine phosphorylation. We found that pretreatment of neonatal rat ventricular myocytes with endothelin-1 rapidly inhibited LIF-induced LIFRalpha tyrosine phosphorylation and Jak1 activation. This effect of endothelin-1 on LIFalpha and Jak1 was attenuated by the MEK1 inhibitor, PD98059, implicating involvement of the ERK kinases. Radioligand binding studies showed that inhibition of LIF signaling resulted from a reduction in cell surface LlFRalpha levels. Additionally, endothelin-1 was found to reduce LIF-induced STAT3 activation, as indexed by STAT3 Y705 phosphorylation. Finally, endothelin-1 and LIF were shown to induce opposite patterns of STAT3 activation in cardiomyocytes. LIF induced rapid, robust STAT3 Y705 phosphorylation; endothelin-1 produced a delayed, modest increase, and initially decreased STAT3 Y705 phosphorylation. Overall our findings indicate that endothelin-1 acts to temper IL-6-related cytokine signaling in cardiomyocytes, in particular STAT3 activation.
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PMID:Cytokine G-protein signaling crosstalk in cardiomyocytes: attenuation of Jak-STAT activation by endothelin-1. 1248 70

Serotonin (5-hydroxytryptamine (5-HT)) is a mitogen of pulmonary artery smooth muscle cells (PASMC) and plays an important role in the development of pulmonary hypertension. Signal transduction initiated by 5-HT involves serotonin transporter-dependent generation of reactive oxygen species and activation of the MEK-ERK pathway. However, the downstream transcriptional regulatory components have not been identified. In systemic smooth muscle cells, GATA-6 has been shown to regulate mitogenesis by driving cells into a quiescent state, and the down-regulation of GATA-6 induces mitogenesis. Thus, the present study tested the hypothesis that 5-HT induces mitogenesis of PASMC by down-regulating GATA-6. Quiescent bovine PASMC were treated with 5-HT, and the binding activity of nuclear extracts toward GATA DNA sequence was monitored. Surprisingly, PASMC express GATA-4, and 5-HT up-regulates the GATA DNA binding activity. Pretreatment of cells with inhibitors of serotonin transporter, reactive oxygen species, and MEK blocks GATA-4 activation by 5-HT. GATA-4 is not activated when the ERK phosphorylation site is mutated, indicating that 5-HT phosphorylates GATA-4 via the MEK/ERK pathway. GATA up-regulation is also induced by other mitogens of PASMC such as endothelin-1 and platelet-derived growth factor. Dominant negative mutants of GATA-4 suppress cyclin D2 expression and cell growth, indicating that GATA-4 activation regulates PASMC proliferation. Thus, GATA-4 mediates 5-HT-induced growth of PASMC and may be an important therapeutic target for the prevention of pulmonary hypertension.
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PMID:Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. 1261 26

Vasoactive peptides are implied in the development of renal sclerosis as evidenced by the efficiency of their antagonists in preventing glomerulosclerosis of experimental and human nephropathies. Genetically engineered models provide a new approach to investigate the mechanisms of the renal profibrotic actions of angiotensin II and endothelin. Overexpression of the human angiotensinogen and renin genes in rats induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed in mice. Transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[1]) and made hypertensive by induction of nitric oxide (NO) deficiency were used to study the renal profibrotic actions of vasoactive peptides. In this strain of mice, luciferase activity is an early index of renal fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were deficient in NO. The pharmacological blockade of angiotensin II and endothelin prevented the development of renal sclerosis without modifying blood pressure. Moreover, when the endothelin receptor antagonist was administered after the development of renal fibrosis, preformed glomerulosclerosis partially regressed. Acute administration of vasoactive peptides and TGF-beta in transgenic procol alpha 2[1] mice showed that the angiotensin II activation of collagen I gene requires participation and/or cooperation of endothelin and TGF-beta. Recent data suggest that the profibrotic actions of vasoactive peptides also need the activation of EGF receptor, ERK and rho kinase pathways in renal and vascular cells.
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PMID:[Vasoactive peptides and the development of renal sclerosis: contribution of transgenes]. 1264 95

Effects of endothelin-1 (ET-1) on glial cell line-derived neurotrophic factor (GDNF) production in cultured astrocytes were examined. Treatment of cultured astrocytes with ET-1 (100 nM) increased mRNA levels of GDNF in 1-6h. The effect of ET-1 was inhibited by BQ788, an ET(B) receptor antagonist, but not by FR139317, an ET(A) receptor antagonist. ET-1 stimulated release of GDNF into culture medium. Dexamethasone (1 microM) and pyrrolidine dithiocarbamate (PDTC, 100 microM), which inhibit activation of NFkappaB, prevented the increases in GDNF mRNA by H(2)O(2). In contrast, the effect of ET-1 was not affected by dexamethasone and PDTC. The increase of astrocytic GDNF mRNA by ET-1 was inhibited by BAPTA/AM (30 microM) and PD98059 (50 microM), but not by calphostin C, staurosporine, and cyclosporine A. These results suggest that ET-1 stimulated expression of astrocytic GDNF through ET(B) receptor-mediated increases in cytosolic Ca(2+) and ERK activation.
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PMID:Endothelin-1 stimulates glial cell line-derived neurotrophic factor expression in cultured rat astrocytes. 1268 49

Recent evidence indicates novel role for matrix metalloproteinases (MMPs), in particular gelatinase A (MMP-2), in the regulation of vascular biology that are unrelated to their well-known proteolytic breakdown of matrix proteins. We have previously reported that MMP-2 can modulate vascular reactivity by cleavage of the Gly32-Leu33 bound in big endothelin-1 (ET-1) yielding a novel vasoactive peptide ET-1[1-32]. These studies were conducted to investigate whether gelatinolytic MMPs could affect neutrophil-endothelial cell attachment. ET-1[1-32] produced by MMP-2 up-regulated CD11b/CD18 expression on human neutrophils, thereby promoted their adhesion to cultured endothelial cells. ET-1[1-32] evoked release of gelatinase B (MMP-9), which in turn cleaved big ET-1 to yield ET-1[1-32], thus revealing a self-amplifying loop for ET-1[1-32] generation. ET-1[1-32] was rather resistant to cleavage by neutrophil proteases and further metabolism of ET-1[1-32] was not a prerequisite for its biological actions on neutrophils. The neutrophil responses to ET-1[1-32] were mediated via activation of ET(A)receptors through activation of the Ras/Raf-1/MEK/ERK signaling pathway. These results suggest a novel role for gelatinase A and B in the regulation of neutrophil functions and their interactions with endothelial cells. Here we describe the methods in detail as they relate to our previously published work.
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PMID:Methods for Analysis of Matrix Metalloproteinase Regulation of Neutrophil-Endothelial Cell Adhesion. 1273 70

Lithium is widely used in the treatment of bipolar disorder, but despite its proven therapeutic efficacy, the molecular mechanisms of action are not fully understood. The present study was undertaken to explore lithium effects of the MEK/ERK cascade of protein kinases in astrocytes and neurons. In asynchronously proliferating rat cortical astrocytes, lithium decreased time- and dose-dependently the phosphorylation of MEK and ERK, with 1 mM concentrations achieving 60 and 50% inhibition of ERK and MEK, respectively, after a 7-day exposure. Lithium also inhibited [3H]thymidine incorporation into DNA and induced a G2/M cell cycle arrest. In serum-deprived, quiescent astrocytes, pre-exposure to lithium resulted in the inhibition of cell cycle re-entry as stimulated by the mitogen endothelin-1: under this experimental setting, lithium did not affect the rapid, peak phosphorylation of MEK taking place after 3-5 min, but was effective in inhibiting the long-term, sustained phosphorylation of MEK. Lithium inhibition of the astrocyte MEK/ERK pathway was independent of inositol depletion. Further, compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta-catenin, consistent with the inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), but failed to reproduce lithium effects on MEK and ERK phosphorylation and cell cycle arrest. In cerebellar granule neurons, millimolar concentrations of lithium enhanced MEK and ERK phosphorylation in a concentration-dependent manner, again through an inositol and GSK-3 beta independent mechanism. These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury.
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PMID:Opposed effects of lithium on the MEK-ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms. 1451 Nov 19

C-type natriuretic peptide (CNP) is known to play a role in the local regulation of vascular tone. We recently found that CNP is also produced by cardiac ventricular cells. However, its local effect on myocyte hypertrophy remains to be elucidated. The present study investigated the effects of CNP on cultured cardiac myocyte hypertrophy and the interaction between CNP and endothelin-1 (ET-1) signaling pathways. CNP attenuated basal and ET-1-augumented protein synthesis, atrial natriuretic peptide secretion, hypertrophy-related gene expression, GATA-4 and MEF-2 DNA binding activities, Ca(2+)/calmodulin-dependent kinase II activity, and ERK phosphorylation. CNP also inhibited ET-1-induced increase in intracellular Ca(2+) concentration. These effects of CNP were mimicked by a cGMP analog, 8-bromo cGMP. However, the inhibitory effects of CNP on the hypertrophic response of myocytes were significantly diminished at high concentrations of ET-1. Although CNP increased intracellular cGMP levels in myocytes, ET-1 suppressed CNP-induced cellular cGMP accumulation. A protein kinase C activator and Ca(2+) ionophore mimicked this suppressive effect of ET-1. We further examined the effect of CNP on the paracrine action of ET-1 secreted from cardiac nonmyocytes. CNP and 8-bromo cGMP significantly inhibited ET-1 secretion from nonmyocytes. Although nonmyocyte-conditioned medium increased the protein synthesis in myocytes through endogenous ET-1 action, this increase was significantly attenuated by pretreatment of nonmyocytes with CNP and 8-bromo cGMP. These findings demonstrate that CNP inhibits ET-1-induced cardiac myocyte hypertrophy via a cGMP-dependent mechanism, and conversely, ET-1 inhibits CNP signaling by a protein kinase C- and Ca(2+)-dependent mechanism, suggesting mutual interference between CNP and ET-1 signaling pathways.
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PMID:Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy: interference between CNP and endothelin-1 signaling pathways. 1508 37

To evaluate the etiologic role of ultraviolet (UV) radiation in acquired dermal melanocytosis (ADM), we investigated the effects of UVA and UVB irradiation on the development and differentiation of melanocytes in primary cultures of mouse neural crest cells (NCC) by counting the numbers of cells positive for KIT (the receptor for stem cell factor) and for the L-3,4-dihydroxyphenylalanine (DOPA) oxidase reaction. No significant differences were found in the number of KIT- or DOPA-positive cells between the UV-irradiated cultures and the non-irradiated cultures. We then examined the effects of UV light on KIT-positive cell lines derived from mouse NCC cultures. Irradiation with UVA but not with UVB inhibited the tyrosinase activity in a tyrosinase-positive cell line (NCCmelan5). Tyrosinase activity in the cells was markedly enhanced by treatment with alpha-melanocyte-stimulating hormone (alpha-MSH), but that stimulation was inhibited by UVA or by UVB irradiation. Irradiation with UVA or UVB did not induce tyrosinase activity in a tyrosinase-negative cell line (NCCmelb4). Levels of KIT expression in NCCmelan5 cells and in NCCmelb4 cells were significantly decreased after UV irradiation. Phosphorylation levels of extracellular signal-regulated kinase 1/2 in cells stimulated with stem cell factor were also diminished after UV irradiation. These results suggest that UV irradiation does not stimulate but rather suppresses mouse NCC. Thus if UV irradiation is a causative factor for ADM lesions, it would not act directly on dermal melanocytes but may act in indirect manners, for instance, via the overproduction of melanogenic cytokines such as alpha-MSH and/or endothelin-1.
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PMID:Effects of ultraviolet light on melanocyte differentiation: studies with mouse neural crest cells and neural crest-derived cell lines. 1501 4

Angiogenesis is necessary for the growth of primary tumors and the formation of metastases. It is well known that vascular endothelial growth factor (VEGF) and its receptors play a major role in this process. To date, the formation of bone metastases has been poorly understood. Tumor cells must interact with the microenvironment of the bone and new blood vessels must spread. The ET/ET(A) (endothelin) receptor system seems to play an important role in this process. Specimens from metastatic bone lesions and non-malignant bone tissue were analyzed by histological and immunohistochemical staining. Sections were stained with antibodies against CD31, Flt-1, KDR, endothelin-1 (ET-1) and endothelin receptor A (ET(A)). Our studies show that there is an increased microvessel density (MVD) in metastatic bone lesions from different primary tumors in contrast to normal bone tissue. In nearly all tumor formations of the bone, ET-1 and its receptor ET(A) was found by immunohistochemistry. We also performed immunohistochemical staining for the VEGF-receptors Flt-1 and KDR. In conclusion, there is an increased vessel density in metastatic bone lesions in contrast to normal bone tissue. The ET/ET(A) system can be detected in nearly all bone specimens and is upregulated in metastatic bone lesions in contrast to healthy bone tissue.
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PMID:Angiogenesis and the ET-1/ETA receptor system: immunohistochemical expression analysis in bone metastases from patients with different primary tumors. 1504 98

The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulators of NGF in cardiomyocytes, we found that endothelin-1 specifically upregulated NGF expression in primary cultured cardiomyocytes. Endothelin-1-induced NGF augmentation was mediated by the endothelin-A receptor, Gibetagamma, PKC, the Src family, EGFR, extracellular signal-regulated kinase, p38MAPK, activator protein-1, and the CCAAT/enhancer-binding protein delta element. Either conditioned medium or coculture with endothelin-1-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. NGF expression, cardiac sympathetic innervation, and norepinephrine concentration were specifically reduced in endothelin-1-deficient mouse hearts, but not in angiotensinogen-deficient mice. In endothelin-1-deficient mice the sympathetic stellate ganglia exhibited excess apoptosis and displayed loss of neurons at the late embryonic stage. Furthermore, cardiac-specific overexpression of NGF in endothelin-1-deficient mice overcame the reduced sympathetic innervation and loss of stellate ganglia neurons. These findings indicate that endothelin-1 regulates NGF expression in cardiomyocytes and plays a critical role in sympathetic innervation of the heart.
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PMID:Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. 1506 13


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