Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Treatment of renal mesangial cells with the vasoconstrictor angiotensin II stimulates a concentration-dependent increase in stress-activated protein kinase (SAPK) activity as measured by phosphorylation of the substrate c-Jun. Time course studies reveal a transient SAPK activation by angiotensin II which is maximal after 5-10 min of stimulation and rapidly declines thereafter to basal levels within 30 min. Using the highly selective angiotensin II AT1 receptor antagonist valsartan, a concentration-dependent inhibition of angiotensin II-induced SAPK activity is observed, clearly implying the AT1-receptor in this angiotensin II-mediated response. To further elucidate the mechanism involved in angiotensin II-induced SAPK activation, cells were treated with different inhibitors. Genistein, a tyrosine kinase inhibitor, greatly blocks (by 90%) the angiotensin II response, whereas pertussis toxin only partially inhibits angiotensin II-activated SAPK activity (by 76%). A highly potent protein kinase C inhibitor [3-[1-[3-(amidinothio)propyl-1H-indoyl-3-yl]-3-(1-methyl-1H- indoyl-3-yl) maleimide methane sulfonate], Ro 31-8220, as well as protein kinase C depletion from the cells by prolonged phorbol ester pretreatment, fail to inhibit the angiotensin II-induced SAPK activation. In summary these results suggest that angiotensin II AT1-receptor is able to activate the SAPK cascade in mesangial cells by a pathway independent of protein kinase C, but requiring both pertussis-toxin-sensitive and -insensitive G-proteins and tyrosine kinase activation.
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PMID:Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype. 957 Apr 79

The purpose of this study was to compare the efficiency of two different Gq protein-coupled receptors (AT1 receptor for angiotensin II and B2 receptor for bradykinin) to activate phospholipase C (PLC). When the receptors were expressed at a similar level of 0.5 pmol/mg of protein, inositol trisphosphate (IP) accumulation elicited by AT1 receptor was four times higher than that elicited by B2 receptor. Genistein and pertussis toxin did not modify AT1 receptor- or B2 receptor-induced IP accumulation. These results indicate that in COS-7 cells, the two receptors activate PLC beta through G proteins of the Gq family. AT1 or B2 receptors were co-expressed with the alpha subunit of either Gq or G11. Both alpha subunits potentiated to the same extent AT1 receptor-induced IP accumulation. alpha 11 was also as efficient as alpha q to potentiate B2 receptor-induced response. Interestingly, however, the potentiating effect of alpha q and alpha 11 was more important (by 5-fold) on AT1 receptor-mediated response than on B2 receptor-mediated response. These results demonstrate that the extent of activation of PLC beta by different Gq-coupled receptors depends on the level of expression of these receptors and on their coupling efficiency. These are important parameters that determine the relative contribution of specific hormones to different biological processes.
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PMID:The bradykinin B2 receptor couples less efficiently than the angiotensin AT1 receptor to the G protein Gq in transiently transfected COS-7 cells. 1063 60

Genistein, a natural isoflavone found in soybeans, exerts a number of biological actions suggesting that it may have a role in cancer prevention. We have previously shown that it potently inhibits OCM-1 melanoma cell proliferation by inducing a G(2) cell cycle arrest. Here we show that genistein exerts this effect by impairing the Cdc25C-dependent Tyr-15 dephosphorylation of Cdk1, as the overexpression of this phosphatase allows the cells to escape G(2) arrest and enter an abnormal chromatin condensation stage. Caffeine totally overrides the genistein-induced G(2) arrest, whereas the block caused by etoposide is not bypassed and that caused by adriamycin is only partially abolished. We also report that genistein activates the checkpoint kinase Chk2 as efficiently as the two genotoxic agents and that caffeine may counteract the activation of Chk2 by genistein but not by etoposide. In contrast, caffeine abolishes the accumulation of p53 caused by all the compounds. Wortmannin does not suppress the Chk2 activation in any situation, suggesting that the ataxia telangiectasia-mutated kinase is not involved in this regulation. Finally, unlike etoposide and adriamycin, genistein induces only a weak response in terms of DNA damage in OCM-1 cells. Taken together, these results suggest that the G(2) checkpoints activated by genistein and the two genotoxic agents involve different pathways.
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PMID:Distinct Chk2 activation pathways are triggered by genistein and DNA-damaging agents in human melanoma cells. 1080 72

Genistein is an isoflavenoid that is abundant in soy beans. Genistein has been reported to have a wide range of biological activities and to play a role in the diminished incidence of breast cancer in populations that consume a soy-rich diet. Genistein was originally identified as an inhibitor of tyrosine kinases; however, it also inhibits topoisomerase II by stabilizing the covalent DNA cleavage complex, an event predicted to cause DNA damage. The topoisomerase II inhibitor etoposide acts in a similar manner. Here we show that genistein induces the up-regulation of p53 protein, phosphorylation of p53 at serine 15, activation of the sequence-specific DNA binding properties of p53, and phosphorylation of the hCds1/Chk2 protein kinase at threonine 68. Phosphorylation and activation of p53 and phosphorylation of Chk2 were not observed in ATM-deficient cells. In contrast, the topoisomerase II inhibitor etoposide induced phosphorylation of p53 and Chk2 in ATM-positive and ATM-deficient cells. In addition, genistein-treated ATM-deficient cells were significantly more susceptible to genistein-induced killing than were ATM-positive cells. Together our data suggest that ATM is required for activation of a DNA damage-induced pathway that activates p53 and Chk2 in response to genistein.
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PMID:The plant isoflavenoid genistein activates p53 and Chk2 in an ATM-dependent manner. 1109 68

1. Human isolated subcutaneous arteries were mounted in a myograph and isometric tension measured. In some experiments, intracellular calcium [Ca(2+)]i was also measured using fura-2. 2. Angiotensin II (100 pM - 1 microM) increased [Ca(2+)]i and tone in a concentration-dependent manner. The effects of angiotensin II (100 nM) were inhibited by an AT1-receptor antagonist, candesartan (100 pM). 3. Ryanodine (10 microM), had no effect on angiotensin II-induced responses, but removal of extracellular Ca(2+) abolished angiotensin II-induced rise in [Ca(2+)]i and tone. Inhibition of Ca(2+) entry by Ni(2+) (2 mM), also inhibited angiotensin II responses. The dihydropyridine, L-type calcium channel antagonist, amlodipine (10 microM), only partially attenuated angiotensin II responses. 4. Inhibition of protein kinase C (PKC) by chelerythrine (1 microM), or by overnight exposure to a phorbol ester (PDBu; 500 nM) had no effect on angiotensin II-induced contraction. 5. Genistein (10 microM), a tyrosine kinase inhibitor, inhibited angiotensin II-induced contraction, but did not inhibit the rise in [Ca(2+)]i, suggesting that at this concentration it affected the calcium sensitivity of the contractile apparatus. Genistein did not affect responses to norepinephrine (NE) or high potassium (KPSS). 6. A selective MEK inhibitor, PD98059 (30 microM), inhibited both the angiotensin II-induced contraction and rise in [Ca(2+)]i, but had no effect on responses to NE or KPSS. 7. AT1 activation causes Ca(2+) influx via L-type calcium channels and a dihydropyridine-insensitive route, but does not release Ca(2+) from intracellular sites. Activation of tyrosine kinase(s) and the ERK 1/2 pathway, but not classical or novel PKC, also play a role in angiotensin II-induced contraction in human subcutaneous resistance arteries.
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PMID:Mechanism of action of angiotensin II in human isolated subcutaneous resistance arteries. 1152 11

The p21(WAF1/Cip1) gene plays a central role in cell cycle regulation. Here we show that topoisomerase II inhibitors, genistein and etoposide, induce p21(WAF1/Cip1) expression mainly in a p53-dependent manner in human lung cancer cell line A549. However, although p53 accumulated, p21(WAF1/Cip1) expression did not depend on the level of Ser15 phosphorylation of p53. Caffeine, an ataxia telangiectasia-mutated (ATM), and ATM- and Rad3-related kinase (ATR) inhibitor, abrogated genistein-induced p21(WAF1/Cip1) and largely blocked etoposide-induced p21(WAF1/Cip1) expression. Wortmannin, an ATM- and DNA-dependent protein kinase inhibitor, partially inhibited p21(WAF1/Cip1) expression induced by genistein and etoposide, whereas UCN-01, a Chk1 inhibitor, partially blocked etoposide, but not genistein-induced p21(WAF1/Cip1) expression. These data suggest that both genistein and etoposide induce p21(WAF1/Cip1) expression in a p53-dependent manner. Genistein appears to stimulate p21(WAF1/Cip1) expression through p53 via ATM, whereas etoposide may activate both ATM and ATR pathways. Our results suggest different mechanisms participate in genistein and etoposide induced p21(WAF1/Cip1) expression.
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PMID:P21 response to DNA damage induced by genistein and etoposide in human lung cancer cells. 1276 22

Genistein, a soy isoflavone, has a wide range of biological actions that suggest it may be of use in cancer prevention. We have recently reported that it arrests hepatoma cells at G2/M phase and inhibits Cdc2 kinase activity. In the present study, we examined the signaling pathway by which genistein modulates Cdc2 kinase activity in HepG2 cells and leads to G2/M arrest, and found that it caused an increase in both Cdc2 phosphorylation and expression of the Cdc2-active kinase, Wee1. Genistein also enhanced the expression of the cell cycle inhibitor, p21waf1/cip1, which interacts with Cdc2. Furthermore, phosphorylation/inactivation of Cdc25C phosphatase, which dephosphorylates/activates Cdc2, was increased. Genistein enhanced the activity of the checkpoint kinase, Chk2, which phosphorylates/inactivates Cdc25C, induced accumulation of p53, and activated the ataxia-telangiectasia-mutated (ATM) gene. Caffeine, an ATM kinase inhibitor, inhibited these effects of genistein on Chk2, p53, and p21waf1/cip1. These findings suggest that the effect of genistein on G2/M arrest in HepG2 cells is partly due to ATM-dependent Chk2 activation, an increase in Cdc2 phosphorylation/inactivation as a result of induction of Wee1 expression, and a decrease in Cdc2 activity as a result of induction of p21waf1/cip1 expression.
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PMID:Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21waf1/cip1 and Wee1. 1475 71

Phytoestrogens are considered to be natural selective estrogen receptor modulators exerting antioxidant activity and improving vascular function. However, the mechanisms responsible for their antioxidative effects remain largely unknown. This study tested the hypothesis that genistein may provide significant endothelial protection by antioxidative effects through attenuating NADPH oxidase expression and activity. The results showed that genistein suppressed the expressions of the p22phox NADPH oxidase subunit and angiotensin II (Ang II) type 1 (AT1) receptor in a concentration- and time-dependent manner in aortic endothelial cells from stroke-prone spontaneously hypertensive rats examined by Western blot analysis. Treatment with genistein also remarkably reduced the Ang II-induced superoxide by the reduction of nitroblue tetrazolium, inhibited nitrotyrosine formation, and attenuated endothelin-1 production by ELISA via the stimulation of Ang II. However, when cells were pretreated with ICI-182780, an estrogen-receptor antagonist, at a concentration of 50 micromol/l for 30 min and then co-incubated with ICI-182780 and genistein for 24 h, the inhibitory effect of genistein was not blocked. In contrast, the inhibitory effect of genistein treatment was partially reversed by 30-min pretreatment of endothelial cells with GW9662, a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist. Genistein thus appears to act as an antioxidant at the transcription level by the downregulation of p22phox and AT1 receptor expression. Our data also showed that the PPARgamma pathway was involved, at least in part, in the inhibitory effect of genistein on the expression of p22phox and AT1 receptors. The endothelial-protective effects of phytoestrogen may contribute to improvement of cardiovascular functions.
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PMID:Genistein inhibits expressions of NADPH oxidase p22phox and angiotensin II type 1 receptor in aortic endothelial cells from stroke-prone spontaneously hypertensive rats. 1575 Feb 62


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