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)

Poly (ADP-ribose) polymerase is a eukaryotic chromosomal enzyme which utilizes the ADP-ribose moiety of NAD to synthesize the nucleic acid homopolymer (ADP-ribose)n (ref. 1). The precise function of (ADP-ribose)n has not been fully established although it does covalently modify chromosomal proteins by ADP-ribosylation. Here we demonstrate that gamma-ray irradiation of lymphoblastoid cells from normal subjects results in depressed DNA synthesis and increased (ADP-ribose)n synthesis. Irradiation of lymphoblastoid cells from patients with the autosomal recessive disease ataxia telangiectasia (AT), however, failed to depress DNA synthesis and did not elevate (ADP-ribose)n levels. We have confirmed that (ADP-ribose)n is synthesized in response to DNA damage and we propose that this polymer may function in the recovery from DNA damage by suppressing DNA synthesis.
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PMID:Unusual levels of (ADP-ribose)n and DNA synthesis in ataxia telangiectasia cells following gamma-ray irradiation. 743 91

Angiotensin II (ANG II) has multiple effects on cardiovascular and renal cells, including vasoconstriction, cell growth, induction of proinflammatory cytokines, and profibrogenic actions. Recent studies provide evidence that ANG II could stimulate intracellular formation of reactive oxygen species (ROS) such as the superoxide anion (O2-). This ANG II-mediated ROS formation exhibits different kinetic and lower absolute concentrations than those traditionally observed during the respiratory burst of phagocytic cells, but it likely involves similar membrane-bound NAD(P)H-oxidases. Current evidence suggests that ANG II, through AT1-receptor activation, upregulates several subunits of this multienzyme complex, resulting in an increase in intracellular O2- concentration. ROS are involved in several signal pathways, and redox-sensitive transcriptional factors (AP-1, NF-kappaB) have been characterized. ANG II-induced ROS play a pivotal role in several pathophysiologic situations of vascular and renal cells such as hypertension, endothelial dysfunction, nitrate tolerance, atherosclerosis, and cellular remodeling. Although these perceptions suggest that drugs interfering with ANG II effects (ACE inhibitors, AT1 -receptor antagonist) may serve as antioxidants, preventing vascular and renal changes, the clinical studies are not so straightforward. In fact, only specific risk groups, such as patients with diabetes mellitus or renal insufficiency, may benefit from ACE inhibitors, whereas hard endpoints showed no advantage for ACE inhibitors in patients with essential hypertension.
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PMID:Free radical production and angiotensin. 1098 Nov 45

Ataxia-telangiectasia (A-T) is a human genetic disorder caused by mutational inactivation of the ATM gene. A-T patients display a pleiotropic phenotype, in which a major neurological feature is progressive ataxia due to degeneration of cerebellar Purkinje and granule neurons. Disruption of the mouse Atm locus creates a murine model of A-T that exhibits most of the clinical and cellular features of the human disease, but the neurological phenotype is barely expressed. We present evidence for the accumulation of DNA strand breaks in the brains of Atm(-/-), supporting the notion that ATM plays a major role in maintaining genomic stability. We also show a perturbation of the steady state levels of pyridine nucleotides. There is a significant decrease in both the reduced and the oxidized forms of NAD and in the total levels of NADP(T) and NADP(+) in the brains of Atm(-/-) mice. The changes in NAD(T), NADH, NAD(+), NADP(T), and NADP(+) were progressive and observed primarily in the cerebellum of 4-month-old Atm(-/-) mice. Higher rates of mitochondrial respiration were also recorded in 4-month-old Atm(-/-) cerebella. Taken together, our findings support the hypothesis that absence of functional ATM results in continuous stress, which may be an important cause of the degeneration of cerebellar neurons in A-T.
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PMID:Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. 1167 83

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which is activated in response to genotoxic insults by binding damaged DNA and attaching polymers of ADP-ribose to nuclear proteins at the expense of its substrate NAD+. In persons affected with ataxia telangiectasia (A-T), associated mutations in the ataxia telangiectasia mutated gene render cells unable to cope with the genotoxic stresses from ionizing radiation and oxidative damage, thus resulting in a higher concentration of unrepaired DNA damage and the activation of PARP in an uncontrolled manner. In primary A-T fibroblasts, we observed a 58-96% increase in PARP activity and a concomitant loss of cellular NAD+ and ATP content. PARP protein by Western blot analysis increased only slightly in these cells, supporting the observation that the steady state levels of DNA damage is higher in A-T cells than in normals. When treated with PARP inhibitors 3-aminobenzamide or 1,5-dihydroisoquinoline, cellular growth rates reached those observed in normal fibroblast cultures. The improvement of cellular growth and NAD+ levels in A-T cells with PARP inhibition suggests that the cellular metabolic status of A-T cells is compromised and the inhibition of PARP may relieve some of the drain on cellular pyridine nucleotides and ATP. Thus, therapy utilizing PARP inhibitors may provide a benefit for individuals affected with A-T.
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PMID:The inhibition of poly(ADP-ribose) polymerase enhances growth rates of ataxia telangiectasia cells. 1205 67

Excess production of superoxide anion in response to angiotensin II plays a central role in the transduction of signal molecules and the regulation of vascular tone. We examined the ability of insulin resistance to stimulate superoxide anion production and investigated the identity of the oxidases responsible for its production. Rats were fed diets containing 60% fructose (fructose-fed rats) or 60% starch (control rats) for 8 weeks. In aortic homogenates from fructose-fed rats, the superoxide anion generated in response to NAD(P)H was more than 2-fold higher than that of control rats. Pretreatment of the aorta from fructose-fed rats with inhibitors of NADPH oxidase significantly reduced superoxide anion production. In the isolated aorta, contraction induced by angiotensin II was more potent in fructose-fed rats compared with control rats. Losartan normalized blood pressure, NAD(P)H oxidase activity, endothelial function, and angiotensin II-induced vasoconstriction in fructose-fed rats. To elucidate the molecular mechanisms of the enhanced constrictor response to angiotensin II, expressions of angiotensin II receptor and subunits of NADPH oxidase were examined with the use of angiotensin II type 1a receptor knockout (AT1a KO) mice. Expression of AT1a receptor mRNA was enhanced in fructose-fed mice, whereas expression of either AT1b or AT2 was unaltered. In addition, protein expression of each subunit of NADPH oxidase was increased in fructose-fed mice, whereas the expression was significantly decreased in fructose-fed AT1a KO mice. The novel observation of insulin resistance-induced upregulation of AT1 receptor expression could explain the association of insulin resistance with endothelial dysfunction and hypertension.
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PMID:Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. 1469 97

Ataxia-telangiectasia (A-T) is a genetic disease, associated with progressive motor impairment and a lack of functional ATM protein. It has been reported that immunoreactive tyrosine hydroxylase and dopamine transporter are reduced in an Atm-/- mouse model of A-T. These observations led to a hypothesis that A-T is associated with loss of nigrostriatal dopamine and prompted the launch of clinical trials to evaluate a therapeutic utility of the anti-parkinsonian drug, l-DOPA. To test for dopamine depletion more directly, we measured regional levels of monoamines and their metabolites in the Atm-/- mouse brain. We also measured levels of NAD+, a cofactor for dopamine biosynthesis and substrate of the DNA damage surveillance enzyme, poly(ADP-ribose) polymerase (PARP). Constitutive activation of PARP has been posited to cause NAD+ depletion. We observed no reduction in monoamine transmitters and no depletion of NAD+, or other high energy phosphate donors in the adult Atm-/- cerebellum, striatum, or ventral mesencephalon. However, our studies did reveal a progressive sensorimotor impairment in Atm-/- mice that may serve as a relevant proxy for progressive neurological impairment in the human disease. Our results call into question the involvement of dopamine in A-T and the therapeutic strategy of enhancing dopaminergic function with l-DOPA.
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PMID:Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia-telangiectasia. 1500 46

Angiotensin II (Ang II) induces a prominent and sustained nitration and activation of ERK1/2 in rat vascular smooth muscle cells, both mediated via AT1 receptor. Nitration and activation was also shown for recombinant non-activated extracellular signal-regulated kinase (ERK) and MEK. Nitration and phosphorylation of ERK1/2 by Ang II was significantly inhibited by NAD(P)H inhibitors and scavengers of oxygen and nitrogen reactive species and completely blocked by a selective inducible nitric-oxide synthase inhibitor. MEK inhibitor U0126 did not affect ERK nitration but completely blocked activation. These data indicate that Ang II nitrates and activates ERK1/2 via a reactive species-sensitive pathway.
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PMID:Angiotensin II induces tyrosine nitration and activation of ERK1/2 in vascular smooth muscle cells. 1613 72

Increased blood pressure induces functional and structural changes of the vascular endothelium. Depression of endothelium-dependant vasodilatation is an early manifestation of endothelial dysfunction due to hypertension. It can be demonstrated by pharmacological or physiological tests. Decreased availability of nitric oxide (NO) is a major determinant of the depression of vasodilatation. It may be caused by a reduction in the activity of NO-endothelial synthase (NOSe) related to: 1) a deficit in substrate (L-arginine), 2) an inhibition by asymmetrical dimethylarginine, 3) a deficit in the cofactor tetrahydrobiopterin (BH4). However, the increase in oxidative stress, a producer of superoxide radicals which combine with NO to form peroxynitrates (ONOO-), is the determining factor. It is related to activation of membranous NAD(P)H oxidases initiated by the stimulation of activating mecanosensors of protein C kinase. The message is amplified by oxidation of BH4 which transforms the NOSe into a producer of superoxide radicals. A cascade of auto-amplification loops leading to atherosclerosis and its complications is then triggered. The superoxide radicals and the peroxynitrates oxidise the LDL-cholesterol. They activate the nuclear factor-kappaB which controls the genes stimulating the expression of many proteins: angiotensinogen and AT1 receptors which stimulate the sympathetic system, receptors of oxidised LDL, adhesion and migration factors (ICAM-1, VCAM-1, E-selectin and MCP-1), pro-inflammatory cytokins (interleukines and TNF-alpha), growth factors (MAP kinases), plasminogen activator inhibitor 1. The monocytes and smooth muscle cells produce metalloproteinases and pro-inflammatory cytokins which destabilise the atheromatous plaque and favourise vascular remodelling. Inshort, the endothelial dysfunction due to hypertension plays a role in a complex physiopathological process and is a marker of future cardiovascular events.
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PMID:[Hypertension, endothelial dysfunction and cardiovascular risk]. 1710 Jan 43

Mechanisms underlying the role of reactive oxygen species (ROS) generated by flavin-containing oxidases in regulating cell cycle progression were examined in human and rodent fibroblasts. Incubation of confluent cell cultures with nontoxic/nonclastogenic concentrations of the flavoprotein inhibitor, diphenyleneiodonium (DPI), reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity and basal ROS levels, but increased proteolysis of cyclin D1, p21(Waf1) and phospho-p38(MAPK). When these cells were allowed to proliferate by subculture in DPI-free medium, an extensive G(1) delay was observed with concomitant activation of p53/p21(Waf1) signaling and reduced phosphorylation of mitogen-activated kinases. Compensation for decreased oxidant generation by simultaneous exposure to DPI and nontoxic doses of the ROS generators, gamma-radiation or t-butyl-hydroperoxide, attenuated the G(1) delay. Whereas the DPI-induced G(1) checkpoint was completely dependent on PHOX91, ATM and WAF1, it was only partially dependent on P53. Interestingly, G(1) to S progression was not affected when another flavin-containing enzyme, nitric oxide synthase, was inhibited nor was it associated with changes in mitochondrial membrane potential. Proliferating cells treated with DPI also experienced a significant but attenuated delay in G(2). We propose that ATM performs a critical function in mediating normal cellular proliferation that is regulated by nonphagocytic NAD(P)H oxidase enzymes activity, which may serve as a novel target for arresting cancer cells in G(1).
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PMID:Regulation of normal cell cycle progression by flavin-containing oxidases. 1763 56

Benzo[a]pyrene (BaP) is a potentially genotoxic and cytotoxic environmental pollutant. Previous studies showed that exposure of HepG(2) cells to BaP causes necrotic cell death [Lin, T., Yang, M.S., 2007b. Cell death induced by benzo[a]pyrene in the HepG(2) cells is dependent on PARP-1 activation and NAD depletion. Toxicology 245, 147-153]. In the present study, the signaling pathways associated with this response was studied. BaP induced accumulation and activation of p53 in HepG(2) cells, which occurred as early as 12h after exposure. Activation of p53 was evidenced by its phosphorylation at serine 15 (Ser15) and acetylation at lysine 382 (Lys382). Chemical inhibition and siRNA-mediated knockdown of p53 expression suppressed its phosphorylation as well as cell death. BaP also activated p38 MAPK and ERK, but not JNK, at 6h after exposure. SB203580 and PD98059, specific inhibitors of p38 MAPK and ERK, respectively, suppressed phosphorylation of p53 at Ser15, but the accumulation of p53 was only moderately reduced. Acetylation of p53 at Lys 382 was not affected by these inhibitors, suggesting that acetylation stabilizes p53 in response to DNA damage. SB203580 and PD98059 prevented downstream energy failure and BaP-induced cell death. Similar results were obtained with siRNA against two isoforms of p38 MAPK, p38alpha and p38beta. Wortmannin, selective inhibitor of DNA-PK and ATM/ATR, abolished p53 phosphorylation, indicating an involvement of multiple pathways of p53 phosphorylation upon exposure to BaP. In summary, the current study demonstrated that both MAPK and p53 activation are required for BaP-induced necrotic cell death. The results also provide a novel model for studying the regulation between p53 and p38 MAPK in the progression of cellular necrosis.
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PMID:MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: involvement of p53 phosphorylation and acetylation. 1840 7


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