UMLS:C0004135 - FACTA Search

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Query: UMLS:C0004135 (ATM)
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1. Angiotensin II (Ang II), the main effector of the renin-angiotensin system, exerts its vasoconstrictory and trophic actions on smooth muscle cells via AT1 receptors. However, Ang II does not act only on smooth muscle cells, as Ang II receptors are also present in endothelial cells. 2. The receptor type on these cells differs depending on the origin of the endothelium and the species. The rat endothelial receptors are mostly of the AT1 type, but AT2 receptors have also been found. The pharmacological characteristics of the AT1 receptors on endothelial cells are similar to those of other cell types. 3. Ang II stimulates phospholipase C and phospholipase A2 activation via the AT1 receptor in endothelial cells. Ang II also stimulates the tyrosine phosphorylation of several proteins in these cells. 4. Some studies suggest that the AT1 receptor mediates the release of vasodilator molecules by endothelial cells and could modulate Ang II effect on smooth muscle cells. Ang II may also inhibit endothelial cell growth via the AT2 receptor. Finally, endothelial Ang II receptors may be implicated in the regulation of fibrinolysis.
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PMID:Angiotensin II receptors in endothelial cells. 934 11

Lipidated angiotensin II (Ang) agonists and antagonists were synthesized and evaluated for their biological activities for eventual use an antimyoproliferative agents. Solid phase peptide synthesis was used for the assembly of the peptides with the Fmoc protection scheme. N-Acetyl-Ser1 Ang was palmitoylated on the serine hydroxyl function. The nonpalmitoylated analogue retained one-third of Ang's affinity toward the AT1 receptor on bovine adrenal cortex membranes, and the palmitoylated analogue was essentially inactive. Upon enzymatic lipolysis or mild saponification of the palmitoylated peptide, biological activity was restored. An analogous compound of Ang, N-acetyl-Ser1,beta-D-naphthylalanine8 ([NAcSer1,D-Nal8]Ang), was a pure antagonist on rabbit aorta but with lower affinity. Its O-palmitoylated form was inactive as well but was easily converted to the nonlipidated active form by lipolysis or saponification. Direct palmitoylation of [sarcosine1]Ang with palmitoyl chloride was obtained on the free phenolic hydroxyl of Tyr4 on solid phase on an otherwise fully protected peptide. This lipopeptide was fully active, was comparable to [Sar1]Ang, and exhibited strongly prolonged activity. Lipolysis and saponification under mild conditions yielded standard [Sar1]Ang. The corresponding [Sar1,D-Nal8]Ang was a potent and very long-lasting antagonist (pA2 = 8.1), and its analogous palmitoyl phenyl ester in position 4 was active in its palmitoylated form (antagonist) and, again, returned to the nonlipidated form upon saponification or lipolysis. [Sar1,Tyr4(O-octadecyl)]Ang, an analogue to Tyr-palmitoylated [Sar1]Ang with an octadecyl phenyl ether in position 4, was also prepared. Surprisingly, the ether compound was inactive. Premature hydrolysis of the palmitoyl phenyl ester peptide was excluded by HPLC analysis, and the activity of the ester peptide is attributed to a putative hydrogen bond that may be critical for biological activity. The discovery of potent biologically active lipidated antagonists of Ang gives access to potential antimyoproliferative agents with numerous application possibilities.
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PMID:Angiotensin analogues palmitoylated in positions 1 and 4. 937 47

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. The traditional RAS is viewed as a system in which circulating Ang II is delivered to target organs and cells. However, in the past decade, a local RAS has been described in cardiac cells, providing evidence for autocrine and paracrine pathways by which biological actions of Ang II could be mediated. The critical actions of Ang II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1 receptor transfected CHO cells. It has been shown that Ang II stimulates the tyrosine phosphorylation and nuclear translocation of Stat1 (Stat 91) and Stat3 (Stat 92). Angiotensin II acting directly through the AT1 receptor, induces the formation of a complex of STAT proteins termed SIF (sis-inducing factor) which binds the DNA sequence, SIE (sis-inducing element) present in the promotor element of many genes. This provides evidence for a direct role of Ang II in mediating inflammatory and remodeling responses through the JAK-STAT pathway. Thus, it is likely that the JAK-STAT pathway has an important role in Ang II-mediated effects on gene transcription, cardiac and vascular cellular growth/development, and inflammatory responses.
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PMID:Molecular mechanisms of angiotensin II in modulating cardiac function: intracardiac effects and signal transduction pathways. 940 64

To investigate potential interactions between angiotensin II (AII) and the insulin signaling system in the vasculature, insulin and AII regulation of insulin receptor substrate-1 (IRS-1) phosphorylation and phosphatidylinositol (PI) 3-kinase activation were examined in rat aortic smooth muscle cells. Pretreatment of cells with AII inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1 by 60%. While AII did not impair insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) beta-subunit, it decreased insulin-stimulated tyrosine phosphorylation of IRS-1 by 50%. AII inhibited the insulin-stimulated association between IRS-1 and the p85 subunit of PI 3-kinase by 30-50% in a dose-dependent manner. This inhibitory effect of AII on IRS-1/PI 3-kinase association was blocked by the AII receptor antagonist saralasin, but not by AT1 antagonist losartan or AT2 antagonist PD123319. AII increased the serine phosphorylation of both the IR beta-subunit and IRS-1. In vitro binding experiments showed that autophosphorylation increased IR binding to IRS-1 from control cells by 2.5-fold versus 1.2-fold for IRS-1 from AII-stimulated cells, suggesting that AII stimulation reduces IRS-1's ability to associate with activated IR. In addition, AII increased p85 serine phosphorylation, inhibited the total pool of p85 associated PI 3-kinase activity, and decreased levels of the p50/p55 regulatory subunit of PI 3-kinase. These results suggest that activation of the renin-angiotensin system may lead to insulin resistance in the vasculature.
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PMID:Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. 941 Aug 92

The objective of this study was to determine whether the G-protein-linked angiotensin II receptor mediated inositol phosphate production involves a tyrosine phosphorylation (tyr phos) dependent pathway in the heart. Cardiomyocytes, in culture, from 7-day-old chick embryonic hearts were incubated with myo [3H] inositol for 18-24 h. Cells were incubated with LiCl to inhibit inositol 1-phosphate phosphatase and allow accumulation of inositol phosphates with angiotensin II (ang II) treatment. Inositol fractions were separated on column chromatography. Ang II produced significant (p < 0.01) increases of InsP1, InsP2, and InsP3, within 1 min of treatment of cardiomyocytes. Tyrosine kinase inhibition with genistein significantly (p < 0.05) reduced ang II induced inositol phosphate production. This did not occur with the analogue diazdien that is a very weak inhibitor of tyrosine kinase. The ability of ang II to induce tyr phos was demonstrated in whole cell lysates of cardiomyocytes immunoprecipitation with anti-P-Tyr antibodies. Genistein blunted this action of ang II. The rapid activation of a tyr phos dependent pathway by ang II was demonstrated by the similar time course of tyr phos of two different cardiac proteins, 70 and 195 kDa, and peak inositol phosphate production. Tyr phos of these cardiac proteins was mediated predominantly but not exclusively through the AT1 and II receptor subtype as it was completely blocked by the AT1 antagonist losartan, while the AT2 receptor antagonist PD123319 blunted ang II-induced tyr phos. These results demonstrate a novel role for a tyr phos dependent pathway in the heart for ang II-induced inositol phosphate production and strengthens the concept of the interaction of G-protein coupled receptors with tyrosine kinases.
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PMID:Angiotensin II-induced inositol phosphate generation is mediated through tyrosine kinase pathways in cardiomyocytes. 941 14

Three DNA damage-responsive cell cycle checkpoints can be shown to operate in diploid human fibroblasts. One checkpoint arrests growth in G1, another inhibits replicon initiation in S phase cells, and the third delays progression from G2 into mitosis. Progression from G2 into M is controlled in part by a cyclin-dependent kinase (cyclin B/Cdk1) that is regulated by tyrosine phosphorylation. Phosphorylation of Tyr15 on Cdk1 is inhibitory for kinase activity. Activation of cyclin B/Cdk1 at the onset of mitosis is accomplished by a phosphatase, Cdc25C, that interacts with cyclin B/Cdk1 in an autocatalytic feedback loop to remove the inhibitory phosphate at Tyr15 and activate kinase activity. DNA damage triggers G2 delay by inhibiting formation of the autocatalytic feedback loop so that dephosphorylation of Tyr15 does not occur. This suppression of activation of cyclin B/Cdk1 appears to account for the failure of damaged G2 cells to progress into mitosis. Once the damage to DNA is repaired, cells resume progression into mitosis as the cycle is re-engaged. The isoflavone genistein inhibits tyrosine kinases, including one that phosphorylates Cdk1 on Tyr15. This kinase, p56/p53lyn is rapidly induced by treatments that trigger cell cycle checkpoints (ionizing radiation, cytosine arabinoside), suggesting that this kinase may actively delay the onset of mitosis by phosphorylating Tyr15 on Cdk1. Genistein also inhibits type II DNA topoisomerase to produce a form of DNA damage that triggers all of the DNA damage-responsive cell cycle checkpoints. A brief 10 min incubation with the topoisomerase poison amsacrine was sufficient to trigger the S phase checkpoint response and inhibit replicon initiation. Inhibition of replicon initiation by 1 microM amsacrine was maximal 20-30 min after drug treatment and by 120 min, the checkpoint response had decayed to allow near control rates of replicon initiation. Topoisomerase II poisons also are powerful clastogens inducing lethal and carcinogenic chromosomal aberrations. Type II topoisomerase can break DNA in a region of chromosome 11q23 that contains the ataxia telangiectasia gene (ATM). The ATM gene controls all of the DNA damage-responsive cell cycle checkpoints. Chromosomal aberrations in 11q23 are frequently seen in acute myeloid leukemia that develops as a consequence of etoposide chemotherapy. Thus, topoisomerase poisons such as genistein may trigger chromatid breakage to inactivate AT gene function, disable cell cycle control, and induce genetic instability.
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PMID:Human topoisomerase II function, tyrosine phosphorylation and cell cycle checkpoints. 949 43

An early event in signaling by the G-protein-coupled angiotensin II (Ang II) AT1 receptor in vascular smooth muscle cells is the tyrosine phosphorylation and activation of phospholipase Cgamma1 (PLCgamma1). In the present study, we show that stimulation of this event by Ang II in vascular smooth muscle cells is accompanied by binding of PLCgamma1 to the AT1 receptor in an Ang II- and tyrosine phophorylation-dependent manner. The PLCgamma1-AT1 receptor interaction appears to depend on phosphorylation of tyrosine 319 in a YIPP motif in the C-terminal intracellular domain of the AT1 receptor and binding of the phosphorylated receptor by the most C-terminal of two Src homology 2 domains in PLCgamma1. PLCgamma1 thus binds to the same site in the receptor previously identified for binding by the SHP-2 phosphotyrosine phosphatase.JAK2 tyrosine kinase complex. A single site in the C-terminal tail of the AT1 receptor can, therefore, be bound in a ligand-dependent manner by two different downstream effector proteins. These data demonstrate that G-protein-coupled receptors can physically associate with intracellular proteins other than G proteins, creating membrane-delimited signal transduction complexes similar to those observed for classic growth factor receptors.
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PMID:Angiotensin II-induced association of phospholipase Cgamma1 with the G-protein-coupled AT1 receptor. 951 77

In cultured vascular smooth muscle cells (VSMC), angiotensin II (ANG II) stimulated tyrosine phosphorylation of multiple proteins including a 130-kDa protein. This 130-kDa protein was identified as a Crk-associated substrate, p130Cas. ANG II-stimulated tyrosine phosphorylation of p130Cas was rapid, concentration dependent, and inhibited by the AT1-receptor antagonist CV-11974. Neither downregulation of protein kinase C by long exposure of cells to phorbol 12,13-dibutyrate nor blockade of Ca2+ mobilization by 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester had an effect on ANG II-stimulated tyrosine phosphorylation of p130Cas. Stimulation with ANG II enhanced the specific association of p130Cas with c-Crk II. The time course of the association of p130Cas and c-Crk II was similar to that of tyrosine phosphorylation of p130Cas. c-Crk II was also tyrosine phosphorylated in response to ANG II. These results indicate that ANG II induces tyrosine phosphorylation of p130Cas and c-Crk II and their specific association, suggesting a potential role of the p130Cas-c-Crk II complex in ANG II signal transduction in VSMC.
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PMID:Tyrosine phosphorylation and association of p130Cas and c-Crk II by ANG II in vascular smooth muscle cells. 957 7

Angiotensin II (Ang II) treatment was recently shown to activate Jak2, Stat1, and Stat3 proteins in cardiac myocytes. Angiotensin-converting enzyme (ACE) inhibitors have been shown to be an effective clinical treatment following myocardial infarction, implying that inhibition of Ang II production is beneficial in this pathological condition. Some of the effects of Ang II in cardiac myocytes may be mediated by the JAK-STAT signaling pathway. The AT1 receptor was the first G-protein-coupled-receptor reported to activate the JAK-STAT pathway. Recently, however, another G-protein-coupled-receptor (i.e. serotonin) was also shown to signal through the JaK2 and STAT proteins in myoblasts. We hypothesized that Ang II treatment might also activate Stat5 transcription factors in cardiac myocytes. In this study, we provide evidence that the G-protein-coupled, Ang II type I (AT1) receptor couples to activation of Stat5 through Jak2 kinase in neonatal rat ventricular myocytes. Angiotensin II induces a 1.5- to 10-fold increase in a Stat5 transcription complex, which binds to the prolactin-inducing element (PIE). By Western analysis, Stat5 protein levels were shown to be tyrosine phosphorylated two- to three-fold over control, following. Ang II treatment of cardiac myocytes. Phosphorylation of Stat5a and Stat5b proteins was rapid and sustained (30-60 min), and Jak2 kinase co-immunoprecipitated with activated Stat5 proteins. In cardiac myocytes, Stat5 proteins co-immunoprecipitated with the AT1 receptor. Selective inhibition of Jak2 kinase with AG-490 blocked formation of prolactin-inducing factor (PIF) complexes by Ang II, suggesting that Jak2 kinase was required for the tyrosine phosphorylation of Stat5 in cardiac myocytes.
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PMID:Angiotensin II activates Stat5 through Jak2 kinase in cardiac myocytes. 960 24

The role of the external third of helix VI of the angiotensin II (AII) AT1 receptor for the interaction with its ligand and for the subsequent signal transduction was investigated by individually replacing residues 252-256 by Ala, and residues 259 or 261 by Tyr, and permanently transfecting the resulting mutants to Chinese hamster ovary (CHO) cells. Binding experiments showed no great changes in affinity of any of the mutants for AII, [Sar1]-AII, or [Sar1, Leu8]-AII, but the affinity for the nonpeptide antagonist DuP753 was significantly decreased. The inositol phosphate response to AII was remarkably decreased in mutants V254A, H256A, and F259Y. These results indicate that AT1 residues Val254, His256, and Phe259 are not involved in ligand binding but participate in signal transduction. Based in these results and in others from the literature, it is suggested that, in addition to the His256 imidazole ring, the Phe259 aromatic ring interacts with the AII's Phe8, thus contributing to the signal-triggering mechanism.
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PMID:Residues Val254, His256, and Phe259 of the angiotensin II AT1 receptor are not involved in ligand binding but participate in signal transduction. 962 56

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