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)

To date, the acquired immunodeficiency syndrome (AIDS) has been identified in over 50 children in the US, including those with associated hemophilia, high-risk environmental factors (Haitian background, parental intravenous drug abuse, or prostitution), and blood transfusions. The evaluation of an infant or young child in whom AIDS is suspected requires exclusion of congenital disorders of immune function. A specific test is not currently available, but inclusion criteria for childhood AIDS have been developed. The diseases accepted as indicative of underlying cellular immunodeficiency children are the same as those used in defining AIDS in adults, with the exclusion of congenital infections such as toxoplasmosis or herpes simplex virus infection in the 1st month of life or cytomegalovirus infection in the 1st 6 months of life. Specific conditions that must be excluded in children are primary immunodeficiency diseases (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia-telangiectasia, neutrophil function abnormality) and secondary immuno-deficiency associated with immunosuppressive therapy, lymphoreticular malignancy, or starvation. Almost all young children with AIDS have hepatosplenomegaly, interstitial pneumonitis, and poor growth. The average age of 36 US child AIDS victims studied in detail was 5 months at presentation with findings suggestive of severe immunodeficiency. Mucocutaneous candidiasis was present in 75% of these 36 children, and Pneumocystis carinii and cytomegalovirus were each isolated from 30% of cases. Normal T4:T8 ratios occur in about 15% of pediatric AIDS cases. Laboratory evidence of polyclonal hypergammaglobulinemia generally supports the AIDS diagnosis. Recurrent infection and malnutrition are major problems in the clinical management of child AIDS patients.
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PMID:Acquired immune deficiency syndrome in childhood. 298 8

Differentiation of NG108-15 neuroblastoma cells following exposure to either 1.5% dimethyl sulfoxide (DMSO)/0.5% fetal bovine serum (FBS) or serum starvation resulted in significant differences in angiotensin (AT) receptor levels and the AT1/AT2 receptor ratio. When NG108 cells were differentiated for 4 days with DMSO/low serum, the number of AT binding sites increased 30-fold compared with the binding levels on undifferentiated (blast) cells. However, cells differentiated by serum starvation for 4 or 14 days resulted in only a modest 2.5- and fivefold increase in AT receptor levels, respectively, over the levels seen with the undifferentiated cells. KD values for all treatment conditions were not significantly different (0.71 +/- 0.11 nM, p = 0.06). Using the AT1 and AT2 isoform-specific receptor antagonists losartan and PD123319, the relative numbers of AT receptor subtypes on undifferentiated and differentiated cells were determined by competitive inhibition against 125I-[Sar1,Ile8]-angiotensin II (sarile). A majority of the AT receptors on undifferentiated NG108 cells were the AT1 subtype (AT1/AT2 receptor ratio of 8:3). Differentiation by serum starvation and DMSO/low serum treatment resulted in fivefold and 30-fold increases in AT receptor levels, respectively, compared with the levels seen with the undifferentiated cells. Although serum starvation increased the total number of AT1 and AT2 receptors, it did not significantly alter the AT1/AT2 receptor ratio. In contrast, differentiation with DMSO/low serum both increased the total number of AT1 and AT2 receptors and reversed the AT1/AT2 receptor ratio (1:3). The increase in AT receptors following differentiation with DMSO/low serum for 4 days was largely accounted for by an 80-fold increase in the AT2 receptor level. Previous studies by Tallant at al. (1991) and Bryson et al. (1992) reported increased AT2 receptor expression following neuroblastoma differentiation with dibutyryl cyclic AMP and DMSO/low serum, respectively, and suggested a role for the AT2 receptor in neuronal differentiation. In the present study, we have extended these earlier observations by demonstrating that the method of differentiation significantly affects both the AT receptor level and the ratio of AT1 to AT2 receptor expression. Finally, our findings indicate that the AT2 receptor is expressed as a consequence of neuronal maturation and dose not mediate morphological differentiation.
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PMID:Differentiation of NG108-15 neuroblastoma cells by serum starvation or dimethyl sulfoxide results in marked differences in angiotensin II receptor subtype expression. 876 61

Fission yeast Cds1 is phosphorylated and activated when DNA replication is interrupted by nucleotide starvation or DNA damage. Cds1 enforces the S-M checkpoint that couples mitosis (M) to the completion of DNA synthesis (S). Cds1 also controls replicational stress tolerance mechanisms. Cds1 is regulated by a group of proteins that includes Rad3, a kinase related to human checkpoint kinase ATM (ataxia telangiectasia mutated). ATM phosphorylates serine or threonine followed by glutamine (SQ or TQ). Here we show that in vitro, Rad3 and ATM phosphorylate the N-terminal domain of Cds1 at the motif T(11)Q(12). Substitution of threonine-11 with alanine (T11A) abolished Cds1 activation that occurs when DNA replication is inhibited by hydroxyurea (HU) treatment. The cds1-T11A mutant was profoundly sensitive to HU, although not quite as sensitive as a cds1(-) null mutant. Cds1(T11A) was unable to enforce the S-M checkpoint. These results strongly suggest that Rad3-dependent phosphorylation of Cds1 at threonine-11 is required for Cds1 activation and function.
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PMID:Threonine-11, phosphorylated by Rad3 and atm in vitro, is required for activation of fission yeast checkpoint kinase Cds1. 1131 65

Here we report the first characterization of replication timing and its regulation in the fission yeast Schizosaccharomyces pombe. We used three different synchronization methods: centrifugal elutriation, cdc10 temperature-shift and release, and starvation for deoxyribonucleoside triphosphates (dNTPs) by treatment with hydroxyurea (HU) followed by removal of HU, to study the times when specific autonomously replicating sequence elements (ARS elements; potential replication origins) replicate during S phase. We found that individual ARS elements replicate at characteristic times, some early and some late, independently of synchronization method. In wild-type cells treated with HU, early ARS elements replicated but late ones did not. However, in HU-treated mutant cells lacking the Rad3 (similar to human ATR and ATM) or Cds1 (similar to human CHK2) checkpoint kinase, both early and late ARS elements were able to replicate. Thus under conditions of dNTP starvation the Rad3 and Cds1 kinases are needed to suppress the replication of normally late-replicating regions.
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PMID:Regulation of replication timing in fission yeast. 1168 51

We identified a novel human AMP-activated protein kinase (AMPK) family member, designated ARK5, encoding 661 amino acids with an estimated molecular mass of 74 kDa. The putative amino acid sequence reveals 47, 45.8, 42.4, and 55% homology to AMPK-alpha1, AMPK-alpha2, MELK, and SNARK, respectively, suggesting that it is a new member of the AMPK family. It has a putative Akt phosphorylation motif at amino acids 595-600, and Ser(600) was found to be phosphorylated by active Akt resulting in the activation of kinase activity toward the SAMS peptide, a consensus AMPK substrate. During nutrient starvation, ARK5 supported the survival of cells in an Akt-dependent manner. In addition, we also demonstrated that ARK5, when activated by Akt, phosphorylated the ATM protein that is mutated in the human genetic disorder ataxia-telangiectasia and also induced the phosphorylation of p53. On the basis of our current findings, we propose that a novel AMPK family member, ARK5, is the tumor cell survival factor activated by Akt and acts as an ATM kinase under the conditions of nutrient starvation.
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PMID:Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. 1240 6

Although ATM, the protein defective in ataxia-telangiectasia (A-T), is activated primarily by radiation, there is also evidence that expression of the protein can be regulated by both radiation and growth factors. Computer analysis of the ATM promoter proximal 700-bp sequence reveals a number of potentially important cis-regulatory sequences. Using nucleotide substitutions to delete putative functional elements in the promoter of ATM, we examined the importance of some of these sites for both the basal and the radiation-induced activity of the promoter. In lymphoblastoid cells, most of the mutations in transcription factor consensus sequences [Sp1(1), Sp1(2), Cre, Ets, Xre, gammaIre(2), a modified AP1 site (Fse), and GCF] reduced basal activity to various extents, whereas others [gammaIre(1), NF1, Myb] left basal activity unaffected. In human skin fibroblasts, results were generally the same, but the basal activity varied up to 8-fold in these and other cell lines. Radiation activated the promoter approximately 2.5-fold in serum-starved lymphoblastoid cells, reaching a maximum by 3 hr, and all mutated elements equally blocked this activation. Reduction in Sp1 and AP1 DNA binding activity by serum starvation was rapidly reversed by exposure of cells to radiation. This reduction was not evident in A-T cells, and the response to radiation was less marked. Data provided for interaction between ATM and Sp1 by protein binding and co-immunoprecipitation could explain the altered regulation of Sp1 in A-T cells. The data described here provide additional evidence that basal and radiation-induced regulation of the ATM promoter is under multifactorial control.
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PMID:Site-directed mutagenesis of the ATM promoter: consequences for response to proliferation and ionizing radiation. 1293 43

It is recognized that brain oxygen deprivation results in increased glycolysis and lactate accumulation. Moreover, glucose metabolism is altered during starvation or diet, resulting in increased plasma ketones (acetoacetate + beta-hydroxybutyrate; BHB). We investigated glucose and lactate adaptation to hypoxia in concurrence with diet-induced ketosis. Male Wistar rats were fed standard (STD), ketogenic (high fat; KG), or carbohydrate-rich (low fat; CHO) diets for 3 wks and then exposed to hypobaric (0.5 ATM) or normobaric atmosphere for 3 wks while on their diets. Lactate, ketones, and glucose concentrations were measured in plasma (mM) and brain tissue (mmol/g). Plasma and tissue ketone levels were elevated up to 12-fold in the KG fed groups compared with other groups (STD and CHO), with the hypoxic KG group reaching the highest levels (2.6 +/- 1.3 mM and 0.3 +/- 0.1 mmol/g; mean +/- SD). Tissue lactate levels in the hypoxic ketotic rats (4.7 +/- 1.3 mM) were comparable with normoxic STD (5.0 +/- 0.7 mM) and significantly lower (ANOVA P < .05) than the hypoxic STD rats (6.1 +/- 1.0 mM). These data indicate that adaptation to hypoxia did not interfere with ketosis, and that ketosis during hypoxia may lower lactate levels in brain, suggesting decreased glycolysis or increased glucose disposal.
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PMID:Adaptation to chronic hypoxia during diet-induced ketosis. 1659 34

Ataxia telangiectasia (A-T) is an autosomal, recessive disorder mainly characterized by neuronal degeneration. However, the reason for neuronal degeneration in A-T patients is still unclear. ATM (A-T, mutated), the gene mutated in A-T, encodes a 370-kDa protein kinase. We measured the levels of the ATM protein found in differentiated neuron-like rat PC12 cells and differentiated neuron-like human SH-SY5Y cells. We found that, in rat PC12 cells, ATM levels decreased dramatically after differentiation, which is consistent with previous results observed in differentiated mouse neural progenitor cells. In contrast, the levels of ATM were similar before and after differentiation in human SH-SY5Y cells. Using an indirect immunofluorescence assay, we showed that ATM translocates from the nucleus to the cytoplasm in differentiated human SH-SY5Y cells. The translocation of ATM was further verified by subcellular fractionation experiments. The constitutive expression and cytoplasmic translocation of ATM in differentiated SH-SY5Y cells suggest that ATM is important for maintaining the regular function of human neuronal cells. Our results further demonstrated that, in response to insulin, ATM protects differentiated neuron-like SH-SY5Y cells from serum starvation-induced apoptosis. These data provide the first evidence that cytoplasmic ATM promotes survival of human neuronal cells in an insulin-dependent manner.
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PMID:Constitutive expression and cytoplasmic compartmentalization of ATM protein in differentiated human neuron-like SH-SY5Y cells. 1724 Nov 56

AMPK is an AMP-activated protein kinase that plays an important role in regulating cellular energy homeostasis. Metabolic stress, such as heat shock and glucose starvation, causes an energy deficiency in the cell and leads to elevated levels of intracellular AMP. This results in the phosphorylation and activation of AMPK. LKB1, a tumor suppressor, has been identified as an upstream kinase of AMPK. We found that in response to treatment with 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), the LKB1 deficient cancer cell line, HeLa, exhibited AMPK-alpha phosphorylation. This indicates the existence of an LKB1-independent AMPK-alpha phosphorylation pathway. ATM is a protein that is deficient in the disease ataxia telangiectasia (A-T). We measured the activation of AMPK by AICAR in the normal mouse embryo fibroblast cell line, A29, and the mouse cell line lacking the ATM protein, A38. In A38 cells, the level of AICAR-induced AMPK-alpha phosphorylation was significantly lower than that found in A29 cells. Furthermore, phosphorylation of AMPK in HeLa and A29 cells was inhibited by an ATM specific inhibitor, KU-55933. Our results demonstrate that AICAR treatment could lead to phosphorylation of AMPK in an ATM-dependent and LKB1-independent manner. Thus, ATM may function as a potential AMPK kinase in response to AICAR treatment.
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PMID:AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner. 1778 44

The Target Of Rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol-3-kinase-related kinases (PIKKs). TOR proteins are found at the core of two distinct evolutionarily conserved complexes, TORC1 and TORC2. Disruption of TORC1 or TORC2 results in characteristically dissimilar phenotypes. TORC1 is a major cell growth regulator, while the cellular roles of TORC2 are not well understood. In the fission yeast Schizosaccharomyces pombe, Tor1 is a component of the TORC2 complex, which is particularly required during starvation and various stress conditions. Our genome-wide gene expression analysis of Deltator1 mutants indicates an extensive similarity with chromatin structure mutants. Consistently, TORC2 regulates several chromatin-mediated functions, including gene silencing, telomere length maintenance, and tolerance to DNA damage. These novel cellular roles of TORC2 are rapamycin insensitive. Cells lacking Tor1 are highly sensitive to the DNA-damaging drugs hydroxyurea (HU) and methyl methanesulfonate, similar to mutants of the checkpoint kinase Rad3 (ATR). Unlike Rad3, Tor1 is not required for the cell cycle arrest in the presence of damaged DNA. Instead, Tor1 becomes essential for dephosphorylation and reactivation of the cyclin-dependent kinase Cdc2, thus allowing reentry into mitosis following recovery from DNA replication arrest. Taken together, our data highlight critical roles for TORC2 in chromatin metabolism and in promoting mitotic entry, most notably after recovery from DNA-damaging conditions. These data place TOR proteins in line with other PIKK members, such as ATM and ATR, as guardians of genome stability.
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PMID:TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions. 1954 37


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