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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding sites for angiotensin II were found, in a line of Swiss 3T3 cells (designated as R3T3 cells), that were insensitive to Dup 753 and dithiothreitol yet were sensitive to PD 123319, making them members of the AT2 class of angiotensin II binding sites. These binding sites appeared not to be coupled to guanine nucleotide-binding proteins, and affinity labeling experiments revealed a specifically labeled protein with an apparent molecular weight of about 100,000. Treatment of cells with angiotensin II revealed no perturbation of common signaling pathways, including stimulation of phosphatidylinositol turnover, effects on levels of cAMP, tyrosine kinase activity, and release of arachidonic acid. Also, angiotensin II or PD 123319 had no effect on cell growth, mitogenesis, or hypertrophy or on mitogenesis or hypertrophy stimulated by several growth factors. These results show that the AT2 binding site is quite distinct from the AT1 site in terms of molecular weight, binding properties, and coupling to second messenger systems. Although the significance of this novel angiotensin II binding site remains obscure, the identification of cell lines selectively expressing it should greatly aid in the understanding of its regulation and function.
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PMID:Characterization of angiotensin II (AT2) binding sites in R3T3 cells. 189 25

Angiotensin II (AII) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in aortic smooth muscle cells (SMC). This trophic effect is mediated by the AT1 subtype of AII receptors. However, very little is known about the cellular signaling pathways involved in this response. In the present study, we examined the role of protein tyrosine phosphorylation in the growth-promoting effects of AII on rat aortic SMC. The addition of AII to quiescent aortic SMC induced tyrosine phosphorylation of multiple substrates, as revealed by antiphosphotyrosine immunoblotting. This response was blocked by preincubation with the AT1-selective antagonist losartan. To explore the functional role of this signaling pathway, we performed experiments with two mechanistically distinct tyrosine kinase inhibitors. Treatment of quiescent aortic SMC with genistein and herbimycin A abolished the stimulatory effect of AII on overall protein tyrosine phosphorylation. Similarly, the two inhibitors prevented AII-induced tyrosine phosphorylation of the cytoskeletal protein paxillin. Under the same conditions, incubation with genistein or herbimycin A did not interfere with AII binding to the AT1 receptor and did not significantly affect AII-stimulated inositol-1,4,5-trisphosphate production and Ca2+ mobilization. In parallel to their selective action on tyrosine phosphorylation, both genistein and herbimycin A completely inhibited AII-stimulated protein synthesis in a dose-dependent manner. In contrast, the two inhibitors were much less potent in preventing the trophic effect of phorbol-12-myristate 13-acetate in these cells. We further demonstrate that genistein and herbimycin A did not prevent mitogen-activated protein kinase activation and c-fos gene induction, which is consistent with the notion that these downstream effectors do not link AII-induced tyrosine phosphorylation to protein synthesis. These results provide evidence that tyrosine phosphorylation has a critical role in cellular hypertrophy and is involved in AII action in vascular SMC.
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PMID:Involvement of a tyrosine kinase pathway in the growth-promoting effects of angiotensin II on aortic smooth muscle cells. 747 82

Our previous study has shown that angiotensin II induces the rapid tyrosine phosphorylation and activation of phospholipase C-gamma 1 in cultured rat aortic smooth muscle (RASM) cells (Marrero, M.B., Paxton, W.G., Duff, J. L., Berk, B. C., and Bernstein, K. E. (1994) J. Biol. Chem, 269, 10935-10939). This signaling pathway is initiated by ligand binding to the AT1 receptor, a cell surface G protein-coupled receptor. Antibodies to pp60c-src were introduced into RASM cells by electroporation. Angiotensin II-stimulated tyrosine phosphorylation of phospholipase C-gamma 1 was eliminated by the anti-pp60c-src antibodies but not by anti-mouse IgG or bovine serum albumin. Angiotensin II also induced the rapid tyrosine phosphorylation of pp120, a known pp60c-src kinase substrate, and this phosphorylation was also specifically inhibited by anti-pp60c-src antibodies. Electroporation of RASM cells with anti-pp60c-src antibodies had no effect on platelet-derived growth factor-stimulated tyrosine phosphorylation of PLC-gamma 1. Anti-pp60c-src also reduced the angiotensin II-stimulated inositol 1,4,5-trisphosphate production by 78%, while it had no effect on the platelet-derived growth factor-stimulated inositol 1,4,5-trisphosphate production. These data provide the first evidence for a direct involvement of pp60c-src kinase in angiotensin II-mediated PLC-gamma 1 phosphorylation and activation. Furthermore, it also describes a pathway in which a seven-transmembrane receptor can stimulate an intracellular tyrosine kinase.
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PMID:Electroporation of pp60c-src antibodies inhibits the angiotensin II activation of phospholipase C-gamma 1 in rat aortic smooth muscle cells. 754 Oct 47

Angiotensin-II (AII), which stimulates steroidogenesis in bovine adrenocortical (BAC) cells through the phosphoinositides pathway, activates p42-p44 mitogen-activated protein kinases (MAPKs) after 5 min of treatment (EC50 = 0.1 nM). This activation is 1) completely inhibited by the AII receptor AT1 subtype antagonist Dup 753 (10 microM), but unaffected by the AT2 antagonist PD 123177; 2) not reproduced by the AT2 agonist CGP 42112A; 3) insensitive to pretreatment with pertussis toxin; and 4) abolished by a 48-h preexposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 microM), which down-regulates protein kinase-C activity. Fibroblast growth factor-2, a potent mitogen for BAC cells, which acts through its tyrosine kinase receptor, also activates MAPK (EC50 = 0.3 in a TPA-insensitive manner, while exhibiting no detectable effect on BAC cell steroidogenesis. In contrast, ACTH, which stimulates steroidogenesis via cAMP and inhibits BAC cell proliferation, does not stimulate MAPK. Indeed, ACTH completely blocks (IC50 = 0.01 nM) the stimulation of MAPK by AII, fibroblast growth factor-2, or TPA. Therefore, bovine adrenocortical cells provide an example of positive and negative hormonal regulation of MAPK activity through a cross-talk between the inositide-, cAMP-, and growth factor-activated tyrosine kinase pathways.
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PMID:Hormonal regulation of mitogen-activated protein kinase activity in bovine adrenocortical cells: cross-talk between phosphoinositides, adenosine 3',5'-monophosphate, and tyrosine kinase receptor pathways. 786 5

Angiotensin II (AII)- and Arg8-vasopressin (AVP)-regulated gene expression in vascular cells has been reported to contribute to vascular homeostasis and hypertrophy. In this report, AVP-induced expression of plasminogen activator inhibitor (PAI)-2 mRNA in rat microvessel endothelial (RME) cells was identified using differential mRNA display. Further characterization of vasoactive peptide effects on PAI expression revealed that AII stimulated a 44.8 +/- 25.2-fold and a 12.4 +/- 3.2-fold increase in PAI-2 mRNA in RME cells and rat aortic smooth muscle cells (RASMC), respectively. AII also stimulated a 10- and 48-fold increase in PAI-1 mRNA in RME cells and RASMC, respectively. These AII effects were inhibited by either Sar1, Ile8-angiotensin or the AT1 antagonist DuP 735, but were not significantly altered in the presence of the AT2 antagonist PD123319. AII stimulation of RASMC and RME cells also significantly increased both PAI-1 protein and PAI activity released to the culture medium. Inhibition of protein kinase C completely blocked PMA-stimulated induction of PAI-2 mRNA in both cell types and inhibited the AII-stimulated increase in RASMC by 98.6 +/- 2.8%. In contrast, protein kinase C inhibition only partially decreased the AII-stimulated PAI-2 expression in RME cells by 68.8 +/- 11.1%, suggesting that a protein kinase C-independent mechanism contributes to a 6.9 +/- 1.5-fold AII induction of PAI-2 expression in endothelial cells. AII and PMA also stimulated protein tyrosine phosphorylation in RME cells, and the tyrosine kinase inhibitor genistein partially blocked their induction of PAI-2 mRNA. These findings suggest that AII may regulate plasminogen activation in the vasculature by inducing both PAI-1 and PAI-2 expression.
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PMID:Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. 788 82

Proliferation of the rat intestinal epithelial cell-line, RIE-1, has previously been shown to be stimulated by certain polypeptide growth factors acting via receptors that possess intrinsic tyrosine kinase activity. In this study, we show that the octapeptide hormone angiotensin II (AII), apparently acting through the AT1 G-protein-coupled receptor, is also a mitogen for RIE-1 cells. Maximal stimulation of DNA synthesis and cellular proliferation occurred at an AII concentration of 10-100 nM, with half-maximal stimulation at 1 nM. The mitogenic response to AII was completely inhibited by the AT1 angiotensin-receptor antagonist, DuP753, but not by the AT2-receptor antagonist, PD123319. The early signalling responses activated by AII in RIE-1 cells include increased production of inositol phosphates, a transient increase in the intracellular concentration of free calcium, an activation of protein kinase C, and a rapid change in the pattern of cellular protein-tyrosine phosphorylation. These results implicate an activation of the inositol lipid signalling pathway via the AT1 receptor subtype in the AII-stimulated mitogenic response of this normal epithelial cell line.
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PMID:Activation of AT1 angiotensin receptors induces DNA synthesis in a rat intestinal epithelial (RIE-1) cell line. 794 4

Many hypertrophic stimuli such as angiotensin II (Ang II) activate phospholipases through G protein-coupled receptors in cardiac myocytes. However, it is not known whether these stimuli also activate the tyrosine phosphorylation-dependent signaling pathway, which plays an essential role in growth factor-induced mitogenic responses in other cell types. Serine/threonine kinases such as mitogen-activated protein (MAP) kinases and 90-kD S6 kinase (RSK) are activated in response to many growth stimuli and are important downstream signaling pathways of tyrosine kinases. Therefore, we examined whether Ang II activates these protein kinases in primary cultures of cardiac myocytes and fibroblasts from neonatal rats. Ang II rapidly induced tyrosine phosphorylation of multiple proteins, including 42-, 44-, 75- to 80-, and 120- to 130-kD proteins, in both cardiac myocytes and fibroblasts. This was accompanied by an increase in tyrosine kinase activity. The 42- and 44-kD proteins were immunologically related to an extracellular signal-regulated kinase family (MAP kinases). Ang II rapidly increased kinase activity of MAP kinases and their downstream kinase, RSK. The Ang II-induced tyrosine phosphorylation and activation of MAP kinases and RSK were AT1 receptor-mediated. Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate or an increase in intracellular Ca2+ by the Ca2+ ionophore A23187 was sufficient to cause tyrosine phosphorylation of multiple proteins and activation of MAP kinase and RSK. Although downregulation of PKC did not suppress Ang II-induced activation of MAP kinase and RSK, chelating intracellular Ca2+ by BAPTA-AM completely abolished Ang II-induced activation of these kinases. Activation of MAP kinases and RSK was also observed in myocytes stimulated with other agonists for Gq protein-coupled receptors, such as phenylephrine, norepinephrine, and endothelin 1, but not with agonists to Gs protein-coupled receptors, such as isoproterenol. These results suggest that Ang II and other hypertrophic stimuli, known to act through Gq protein-coupled receptors, rapidly cause tyrosine phosphorylation of several intracellular substrates through activation of tyrosine kinase and activate MAP kinases and RSK in cardiac myocytes as well as in cardiac fibroblasts. Furthermore, intracellular Ca2+, rather than PKC, seems to be critical for Ang II-induced activation of these protein kinases in cardiac myocytes.
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PMID:Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. The critical role of Ca(2+)-dependent signaling. 800 Dec 66

In guinea pig gastric longitudinal (LM) and circular (CM) muscle strips, angiotensin-II (Ang-II) caused a concentration-dependent contraction that required extracellular calcium and that could not be attributed to the secondary release of agonists from neural elements. Contractions in both the LM and CM were blocked by the Ang-II AT1 receptor antagonist, Losartan (DuP 753, pA2 9.1) but not by the AT2 antagonist, PD 123319. However, in the LM preparation, indomethacin (3 microM) blocked Ang-II-mediated contraction, whereas in the CM contraction was resistant to indomethacin. Contractions caused by Ang-II in the CM preparations were also unaffected by inhibitors of leukotriene biosynthesis, but were partially (58%) inhibited by the cytochrome P450 monooxygenase inhibitor, ketoconazole. The diacylglycerol lipase inhibitor, U57,908, at a concentration (20 microM) that completely blocked the contractile action of epidermal growth factor in the LM, caused a substantial inhibition of Ang-II-mediated contraction in both the LM (55% inhibition) and CM (75% inhibition). The phospholipase A2 inhibitor, mepacrine caused a modest inhibition (24%) of contraction in both preparations. In the presence of U57,908, mepacrine further inhibited contraction caused by Ang-II in the LM preparation. The tyrosine kinase (YK) inhibitors, genistein and tyrphostin (RG 50864) selectively and completely blocked Ang-II-mediated contraction in the LM, without affecting contractions caused by carbachol and bradykinin. In the CM preparation, the two YK inhibitors were selective, but only partially (40-60%) blocked Ang-II-mediated contraction, without affecting contractions caused by bradykinin and carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Distinct signal transduction pathways for angiotensin-II in guinea pig gastric smooth muscle: differential blockade by indomethacin and tyrosine kinase inhibitors. 843 35

Angiotensin II (Ang II) is a potent regulator of proximal tubule functions, including transport, metabolism, and cell proliferation. The opossum kidney (OK) cell line is a useful model of renal proximal tubule. Mitogen-activated protein (MAP) kinases are rapidly phosphorylated and activated in response to various agonists. We investigated Ang II effects on serine/threonine kinase cascades in OK cells. The major findings of the present study are that Ang II stimulated MAP kinase kinase (MAPKK), MAP kinase (MAPK), and S6 kinase activities, and that it increased phosphorylation of Raf-1 kinase and p42 MAP kinase in OK cells. These stimulations of kinases were dose-dependent (from 10(-6) to 10(-11) M). The time course of activation was sequential; the peak stimulation was reached at 5 to 10 minutes for Raf-1 kinase, MAPKK and MAPK, and at 20 minutes for S6 kinase. The activation of MAPK was inhibited by approximately 70% with prolonged 24-hour PMA pretreatment or in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein and herbimycin) did not inhibit AngII-induced MAPK activity. This activation of MAPK was also inhibited via AT1 receptor antagonist, Dup753 and pertussis toxin. This evidence suggests that the activation of serine/threonine cascades by Ang II is largely dependent on PMA-sensitive PKC, and is not dependent on tyrosine kinase and pertussis toxin.
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PMID:Sequential activation of MAP kinase cascade by angiotensin II in opossum kidney cells. 858 39

The ATDC gene was originally identified by its ability to complement the radiosensitivity defect of an ataxia telangiectasia (AT) fibroblast cell line. Because hypersensitivity to ionizing radiation is an important feature of the AT phenotype, we reasoned that ATDC may function generally in the suppression of radiosensitivity. Previous work in our laboratory focused on radiosensitization mechanisms in human squamous carcinoma (SC) cells, especially A431 cells. To establish a basis for investigating the role of ATDC in radiation-responsive signaling pathways in human SC cells, we characterized ATDC message and protein expressions in A431 cells. ATDC message expression was also compared among human epidermoid cells (A431 cells, HaCaT spontaneously immortalized human keratinocytes and normal human epidermal keratinocytes) and a normal human fibroblast cell line (LM217). We made the following major observations: (i) the relative abundance of ATDC message is substantially higher in the epidermoid cells than in the fibroblast cell line, which has a message level comparable to those reported for other fibroblast lines; (ii) ATDC is constitutively phosphorylated on serine/threonine in A431 cells; (iii) in A431 cells, ATDC is a substrate for the serine/threonine protein kinase C (PKC) but not the epidermal growth factor (EGF) receptor tyrosine kinase; and (iv) EGF decreases ATDC message and protein expressions in A431 cells after a 24-hr exposure. The phosphorylation studies suggest that the ability of ATDC to modulate cellular radiosensitivity may be mediated in part through a PKC signaling pathway.
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PMID:Expression of the ATDC (ataxia telangiectasia group D-complementing) gene in A431 human squamous carcinoma cells. 864 48


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