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)

Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439). There were four microcephalic XP blood relatives and none in the FA or A-T families. In the A-T families, idiopathic scoliosis and vertebral anomalies were in excess, while genitourinary and distal limb malformations were found in the FA families. A-T, FA, or XP heterozygotes may constitute an important proportion of individuals at risk for specific malformations or developmental abnormalities.
Am J Hum Genet 1982 Sep
PMID:Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families. 712 32

Skin fibroblasts from ataxia telangiectasia and xeroderma pigmentosum (XP) donors and from the XP sib (possible heterozygote), all genetically predisposed to a high risk of cancer, show an increased susceptibility to light-induced chromatid breaks after culture in vitro. Light-induced chromatid breaks were shown previously to result from generation of hydrogen peroxide (H2O2) during light exposure. The level of susceptibility attained is significantly higher than that observed in 13 lines of fibroblasts from normal skin of donors ranging in age from 3 days to 92 years or from fetal skin tested at various population doubling levels. Two lines of normal skin fibroblasts transformed by chemical carcinogens to neoplastic cells also show a significant increase in susceptibility as compared with their untransformed controls. These data indicate for human cells, as reported earlier for mouse cells, an association between enhanced susceptibility to light-induced chromatid damage and neoplastic potential; this association is further supported by the high susceptibility of cells derived from a human adenocarcinoma. Two observations are consistent with the concept that the increased susceptibility does not result from greater initial damage to the DNA of the neoplastic cells. First, activities of the ubiquitous H2O2 scavenging enzyme, glutathione peroxidase, are similar in the paired normal and neoplastic cell populations. Second, cells of the paired lines are equally sensitive to DNA breakage by exogenous H2O2. The enhanced susceptibility associated with neoplastic potential may result from an impaired capacity to repair DNA rather than a greater initial sensitivity of the neoplastic cells to the damaging agent.
Int J Cancer 1981 Sep 15
PMID:Light-induced chromatid damage in human skin fibroblasts in culture in relation to their neoplastic potential. 731 76

The capacity of cultured fibroblast-like cells from 5 ataxia telangiectasia (AT) patients to repair gamma-ray-induced damage formed in DNA under aerobic conditions was measured by unscheduled DNA synthesis (UDS). The AT cultures exhibited generally reduced UDS compared to the normal cultures for gamma-ray doses of 4--12 kR. Reduced UDS in the AT cultures was observed for repair-incubation periods at which UDS was not saturated (0.5 and 1 h), and for periods characterized by maximal amounts of UDS in both the normal and AT cultures (2 and 4 h). The results suggest a class of lesions repairable in the normal cells by UDS within 1 h may persist in the AT cells for 4 h or longer.
Mutat Res 1980 Sep
PMID:Unscheduled DNA synthesis in cultured ataxia telangiectasia fibroblast-like cells. 744 94

The peptide hormone angiotensin II (AngII) plays a principal role in regulating blood pressure and fluid homeostasis. Most of its known effects are mediated by a guanine nucleotide-regulatory protein (G protein)-coupled receptor pharmacologically defined as the type-1 AngII receptor or AT1. Characterization of cDNA and genomic clones shows that the human AT1 gene contains five exons and encodes two receptor isoforms as a result of alternative splicing. Exon 5 contains the previously characterized open reading frame for AT1, and exons 1 to 3 are alternatively spliced upstream of it to generate several mRNA species, while transcripts containing exon 4 are of minor abundance. In an in vitro translation system, the presence of exon 1 was found to be extremely inhibitory to translation, probably because it can form a stable secondary structure at the RNA level. The alternatively spliced second exon also had a strong inhibitory effect on translation, presumably because it contains a minicistron commencing with an ATG in an optimal context for translation initiation. Exon 2 was similarly inhibitory to protein production in transfected cells, but exon 1 was found to enhance protein synthesis in this system. Transcripts containing exon 3 and 5, which comprise up to one-third of AT1 mRNAs in all tissues examined, encode a receptor with an amino-terminal extension of 32-35 amino acids. These transcripts were translated into a larger receptor isoform in vitro and produced a functional receptor with normal ligand binding and signaling properties in transfected cells.
Mol Endocrinol 1995 Sep
PMID:Alternatively spliced human type 1 angiotensin II receptor mRNAs are translated at different efficiencies and encode two receptor isoforms. 749 Nov 17

The angiotensin II antagonistic activity of SB 203220, [E-alpha-[[2-butyl-1-(4-carboxy-1-naphthalenyl)methyl]-1H- imidazol-5-yl]-methylene]-2-thiophene-propanic acid], was examined in several in vitro and in vivo assays. SB 203220 displaced [125I]angiotensin II binding from a variety of tissues including the cloned human AT1 receptor (IC(50)5-15 nM). SB 203220 (10 microM) did not interact with AT2, endothelin (ETA and ETB) or calcitonin gene-related peptide receptors. [3H]SB 203220 bound with high affinity to the AT1 receptor (Kd = 4.9 nM), but dissociated from the receptor at a much slower rate when compared to [3H]SK&F 108566. SB 203220 antagonized intracellular Ca2+ mobilization induced by angiotensin II in rat vascular smooth muscle cells and exhibited a selective and partially insurmountable antagonism of angiotensin II-induced contraction in isolated rabbit aorta. In the aorta, SB 203220 produced a concentration-dependent parallel shift in the concentration-response curve to angiotensin II [EC30 = 5.94 +/- 1.6 10(-11) M] and depressed the maximal contractile response to angiotensin II by approximately 35%. The antagonistic effect of SB 203220 in rabbit aorta was slowly reversible compared to SK&F 108566. SB 203220 displayed no agonist activity and had no effect on the contractile responses to KCl, endothelin-1 or norepinephrine. In rats, SB 203220 at 10 mg/kg i.v. inhibited angiotensin II-induced aldosterone release. Intraduodenal or oral administration of SB 203220 (1-10 mg/kg) to conscious rats and dogs inhibited the pressor responses to exogenous angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
Eur J Pharmacol 1995 Sep 05
PMID:Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist. 749 22

Thyroid dysfunction produces marked cardiovascular responses; the renin-angiotensin system (RAS) is important in control of the cardiovascular system. We have measured changes in the plasma RAS and in angiotensin II (AT) receptors in experimentally hyperthyroid, euthyroid, or hypothyroid rats. Hyperthyroidism activated the plasma RAS, increasing plasma angiotensinogen by 85% after 7-day triiodothyronine (T3) treatment, plasma renin activity (PRA) by 47% and concentration by 52%, and plasma AT by 1.250%. Hypothyroidism reduced plasma angiotensinogen by 71%, PRA by 73%, and plasma AT by 81% without altering plasma renin concentration (PRC). Plasma aldosterone was reduced by 39% in hyperthyroid rats and by 95% in hypothyroid rats. AT receptors were characterized in heart, liver, adrenal gland, and kidney. Cardiac, liver, and kidney AT receptor densities increased in hyperthyroidism by 73, 113, and 75%, respectively; adrenal gland receptor density decreased by 39%. Similar results were observed in hypothyroidism except that adrenal gland receptor density was markedly increased by 205%. AT receptor subtypes were characterized in ventricular homogenates by the selective antagonist losartan. Hyperthyroidism markedly increased AT2-subtype density by 204% in left ventricle, and by 304% in right ventricle and decreased AT1-subtype density by 38% and 31% in left and right ventricles, respectively. AT2-subtype density increased by 168% in hypothyroid rats; AT1-subtype density was unchanged. Thyroid dysfunction causes significant changes in the RAS and in AT receptor density, especially of the AT2 subtype. Although a physiological function has not yet been reported for AT2 receptors, our results suggest that selective AT2-receptor antagonists may prove therapeutically useful in treatment of cardiovascular disease in thyroid dysfunction.
J Cardiovasc Pharmacol 1993 Sep
PMID:Renin-angiotensin system in thyroid dysfunction in rats. 750 37

Since dietary salt loading enhances nitric oxide (NO) generation in the kidney, we investigated the hypothesis that changes in salt intake have specific effects on vascular resistance in the kidney mediated by the L-arginine-NO pathway. We contrasted changes in renal and hindquarter vascular resistances (RVR and HQVR) in anesthetized rats during intravenous infusions of graded doses of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Groups (N = 8 to 10) of rats were maintained on a high salt (HS) or low salt (LS) diet for two weeks. Compared to those on LS, rats on HS had a greater increase in mean arterial pressure (delta MAP; +32 +/- 4 vs. +22 +/- 3%; P = 0.05) and RVR (+160 +/- 17 vs. +83 +/- 10%; P < 0.005) and a greater fall in renal blood flow (delta RBF; -47 +/- 3 vs. -32 +/- 4%; P < 0.01); changes in HQVR were similar in the two groups. The enhanced RVR response to L-NAME in HS rats could not be ascribed to the higher renal perfusion pressure (RPP) since it persisted in rats whose RPP was controlled by adjustment of a suprarenal aortic clamp. Changes in RVR with an NO donor (SIN-1) were similar in HS and LS rats. L-NAME reduced plasma renin activity in both HS and LS rats. After inhibition of ACE with captopril, or of angiotensin II type I (AT1) receptor with losartan, the increase in RVR with L-NAME remained greater in HS than LS rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Kidney Int 1994 Sep
PMID:Renal vasoconstriction during inhibition of NO synthase: effects of dietary salt. 752 72

Intra- and postoperative blood loss during open heart surgery is reduced by approximately 50% when aprotinin, a potent inhibitor for plasmin and kallikrein, is administered during surgery. But whether aprotinin increases the risk of thrombotic complications remains controversial. The aim of this study was to evaluate the effects of aprotinin administration on coagulation and fibrinolysis during and after cardiopulmonary bypass (CPB). Thirty patients undergoing CPB were randomly assigned to two comparable groups for a double-blind study (16 patients receiving high-dose aprotinin, 14 patients receiving placebo). Patients' plasma levels of ATM (thrombin-induced modified antithrombin III), FbDP (fibrin degradation products, D-Dimers), t-PA (tissue-type plasminogen activator) and PAI-1 (plasminogen activator inhibitor type 1) were measured at regular intervals. In both groups, ATM level increased during surgery (from less than 30 to 90-110 ng/ml) and returned to normal 24 h after surgery and remained unchanged thereafter. Aprotinin reduced this increase in ATM levels (p = 0.02 at 30 min after the start of CPB). The FbDP generated during surgery was greatly reduced in the aprotinin group (945 ng/ml) in comparison with the placebo group (1889 ng/ml, p = 0.004). After surgery, FbDP levels decreased in both groups with nadirs at 2nd day (placebo group: 940 ng/ml and aprotinin group: 865 ng/ml) indicating a hypofibrinolytic period. Then, the FbDP level in both groups started to increase up to the 9th day, in an identical manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Thromb Haemost 1994 Sep
PMID:Postoperative hemostasis and fibrinolysis in patients undergoing cardiopulmonary bypass with or without aprotinin therapy. 753 77

Patients with the genetic disorder ataxia telangiectasia (AT) have mutations in the AT mutated (ATM) gene, which is homologous to TEL1 and the checkpoint gene MEC1. A tel1 deletion mutant, unlike a mec1 deletion, is viable and does not exhibit increased sensitivity to DNA-damaging agents. However, increased dosage of TEL1 rescues sensitivity of a mec1 mutant, mec1-1, to DNA-damaging agents and rescues viability of a mec1 disruption. mec1-1 tel1 delta 1 double mutants are synergistically sensitive to DNA-damaging agents, including radiomimetic drugs. These data indicate that TEL1 and MEC1 are functionally related and that functions of the ATM gene are apparently divided between at least two S. cerevisiae homologs.
Cell 1995 Sep 08
PMID:TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. 754 45

We examined the pharmacological properties of U-97018, a novel nonpeptide angiotensin II (AII) receptor antagonist, in various in vitro and in vivo studies. U-97018 selectively displaced 125I-AII specific binding in the membrane fraction derived from the rat mesenteric artery and adrenal cortex (AT1 subtype) with IC50 of 1.3 +/- 0.2 and 7.7 +/- 1.3 nM, respectively, without altering the AII binding of the rat adrenal medulla (AT2 subtype). In rat adrenal cortical cells, U-97018 inhibited 1 nM AII-induced aldosterone secretion with an IC50 of 0.48 nM; it shifted concentration-secretion response curve for AII to the right and inhibited the maximal response to AII, yielding a pKB of 9.8. Similarly, U-97018 showed insurmountable antagonism with a pKB of 10.6 against the AII-induced contraction in the isolated rabbit aorta. U-97018 had no direct effect on the activities of renin and angiotensin converting enzyme in vitro. In pithed rats, U-97018 inhibited the AII-induced pressor response with an ED50 of 0.28 mg/kg, i.v. without any partial agonistic activity. In anesthetized rats and dogs, intraduodenal administration of U-97018 at a dose of 1 mg/kg inhibited the AII-induced pressor response by about 60%. In spontaneously hypertensive rats, U-97018 at 10 mg/kg p.o. produced antihypertensive effects which lasted for 24 hr after administration. Thus, U-97018 is an orally active, insurmountable AII receptor antagonist without any agonistic activity.
J Pharmacol Exp Ther 1995 Sep
PMID:Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, U-97018. 756 67


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