Endothelin Stimulatessis-Inducing Factor-like DNA Binding Activity in CHO-K1 Cells Expressing ETAReceptors

doi:10.1006/bbrc.1996.0545

Biochemical and Biophysical Research Communications

Volume 221, Issue 1, 5 April 1996, Pages 62-66

https://doi.org/10.1006/bbrc.1996.0545 Get rights and content

Abstract

ET-1, a member of the family of peptides known as endothelins, binds to a G-protein-coupled receptor, ET_A, and stimulates a variety of cellular responses, including contraction, growth, and mitogenesis. ET-1 stimulation of a chinese hamster ovary cell line stably transfected with the ET_Areceptor (CHO/ET_A) induced formation of SIF (sis-inducing factor), a key component of the STAT (SignalTransducers andActivators ofTranscription) pathway, in a concentration-dependent manner. SIF induction was blocked by a specific inhibitor of ET_A, BQ610, and by genistein, a tyrosine kinase inhibitor. This report demonstrates that ET-1 stimulates the STAT pathway of signal transduction through a G-protein-coupled receptor, ET_A, in this stably transfected cell line.

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Cited by (21)

Phosphorylation of JAK2 by serotonin 5-HT<inf>2A</inf> receptor activates both STAT3 and ERK1/2 pathways and increases growth of JEG-3 human placental choriocarcinoma cell
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However, the presence of this motif remains to demonstrate within the 5-HT2A receptor protein. Endothelin and thrombin, both Gq-coupled receptors, also activate JAK2-STAT pathways [1,37,38]. Although a direct association of these receptors with the JAK2 molecule is controversial, we have previously demonstrated by immunoprecipitation that a physical association between the 5-HT2A and JAK2 protein occurs in choriocarcinoma cell lines [6].
Serotonin 5-HT_2A receptor activation improves viability, increases DNA synthesis and activates JAK2-STAT3 and MEK1/2-ERK1/2 signalling pathways in JEG-3 human trophoblast choriocarcinoma cells. The goal of this study was to characterize the signal transduction cascade involved in 5-HT_2A receptor-induced growth of JEG-3 cells. Selective 5-HT_2A receptor agonist, DOI, induced JEG-3 cell growth was inhibited by the inhibitor of JAK2 (AG490), MEK1/2 (U0126), phospholipase C-β (PLC-β; U73122) and protein kinase C-β (PKC-β; Gö6976)), whereas the selective phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) had no effect. Specific inhibitors of PLC-β, PKC-β and Ras (farnesylthiosalicylic acid) inhibit activation of ERK1/2, whereas the PKC-ζ inhibitor GF109203X had no effect. Interestingly, inhibition of JAK2 prevented DOI-induced phosphorylation of ERK1/2 whereas inhibition of ERK1/2 pathway had no effect on DOI-induced activation of STAT3. Taken together, our results demonstrate that both the JAK2-STAT3 and PLC-β-PKC-β-Ras-ERK1/2 signalling pathways are involved in the stimulation of JEG-3 cell growth mediated by DOI. Moreover, this study shows that activation of JAK2 by the 5-HT_2A receptor is essential to activate both STAT3 and ERK1/2 signalling pathways as well as to increase JEG-3 choriocarcinoma cell growth and survival.
Involvement of STAT5a signaling in morphine-induced up-regulation of the cyclin D1
2009, Biochemical Pharmacology
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Some evidence from previous studies supports this hypothesis. For example, many GPCRs agonists may bring about activation of STATs and changes in gene transcription [33,34], indicating that there are variations in the mechanism of activation among the different receptors including opioid receptors. Moreover, the consensus motif YXXL present in the opioid receptor may interact with STAT5 which in turn can be phosphorylated by Src kinase [33,35].
Opioid receptors and cytokine receptor have been verified to have a functional link and interaction. However, the pathway by which opioid receptor in lymphocytes is linked to cytokine signaling is not well defined. Using confocal microscopy and Western blotting this study showed that morphine treatment was able to activate cytoplasmic STAT5a in CEM x174 cells, which then translocated into the nucleus and bound to elements of the cyclin D1 promoter. As a consequence the expression of the cyclin D1 was apparently up-regulated. The data from EMSA–superEMSA and ChIP-qPCR further confirmed that morphine was capable of promoting the binding of STAT5a to its elements (proximal and distal), and this was abolished by the antagonist naloxone. As shown by transient transfection assay, activity of the cyclin D1 promoter was significantly reduced by 82% (distal) and 65% (proximal) after two STAT5a elements were mutated in comparison with wild type STAT5a elements. Moreover, knockdown of STAT5a was associated with a concurrent silencing of morphine-induced expression of cyclin D1, demonstrating involvement of STAT5a in morphine-triggered signaling in the regulation of cyclin D1 expression. The finding provides evidence which demonstrates that there is cross-talk between the mu opioid receptor and cytokine signaling in lymphocytes. Thus, we conclude that morphine may modulate cyclin D1 gene expression via signal transducers and activators of transcription (STATs) signaling, which will be beneficial for further understanding of the pharmacological effect of morphine on immune regulation.
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Endothelin-1 activation of JAK2 in vascular smooth muscle cells involves NAD(P)H oxidase-derived reactive oxygen species
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Endothelin-1 (ET-1) and JAK2 are both implicated in diabetic complications. Therefore, we investigated whether ET-1 differentially actives JAK2 under conditions of normal (5 mM) and high (25 mM) glucose. We tested the hypothesis that reactive oxygen species mediate the activation of JAK2 in response to ET-1. In rat aortic vascular smooth muscle cells (VSMC), ET-1 (10⁻ ⁷ M, 5 min) stimulated the activation of JAK2, which was further enhanced under high glucose conditions. Allopurinol (xanthine oxidase inhibitor, 1 μM) and l-NAME (nitric oxide synthase inhibitor, 1 mM) had no effect on ET-1-induced JAK2 activation, while apocynin (NAD(P)H oxidase inhibitor 100 μM) resulted in a significant inhibition of ET-1-induced JAK2 and MAPK activation. Overexpression of SOD did not inhibit ET-1-induced activation of JAK2, but catalase (50 units/mL) treatment resulted in complete inhibition. In vivo administration of apocynin (1.5 mM) resulted in a significant decrease (∼ 50%), while the ET_A receptor antagonist ABT-627 completely inhibited phosphorylation of JAK2 in aortae from STZ-induced diabetic rats. Additionally, DHE staining of aortic sections was significantly reduced in diabetic rats treated with ABT-627. These data suggest that in VSMC, ET-1 via the ET_A receptor, utilizes NAD(P)H oxidase to activate JAK2.
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2000, Biochemical and Biophysical Research Communications
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It has been 100 years since the discovery of renin by Tigerstedt and Bergman. Since that time, numerous discoveries have advanced our understanding of the renin–angiotensin system, including the observation that angiotensin II is the effector molecule of this system. A remarkable aspect of angiotensin II is the many different physiological responses this simple peptide induces in different cell types. Here, we focus on the signal transduction pathways that are activated as a consequence of angiotensin II binding to the AT₁ receptor. Classical signaling pathways such as the activation of heterotrimeric G proteins by the AT₁ receptor are discussed. In addition, recent work examining the role of tyrosine phosphorylation in angiotensin II-mediated signal transduction is also examined. Understanding how these distinct signaling pathways transduce signals from the cell surface will advance our understanding of how such a simple molecule elicits such a wide variety of specific cellular responses.

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¹: Correspondence to: Kenneth M. Baker, M.D., Weis Center for Research, 26-11, 100 North Academy Avenue, Danville, PA 17822; Fax: (717)271-6668.

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Regular ArticleEndothelin Stimulatessis-Inducing Factor-like DNA Binding Activity in CHO-K1 Cells Expressing ETAReceptors

Abstract

Regular Article
Endothelin Stimulatessis-Inducing Factor-like DNA Binding Activity in CHO-K1 Cells Expressing ET_AReceptors