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 macrolide FK-506, like the cyclic undecapeptide cyclosporin A (CsA), is a potent immunosuppressant that interferes with the transcriptional activation of several early-phase genes in T lymphocytes, including that for interleukin-2 (IL-2). We compared the effects of FK-506 and CsA on transcription from the 5' upstream activating sequences (UAS) of the human IL-2 gene and several cellular and viral UAS to define cis-acting sites which may be responsive to FK-506. The UAS surveyed included the human IL-2 receptor alpha-chain, human metallothionein II, simian virus 40 early, human cytomegalovirus immediate-early, adenovirus major late, and Rous sarcoma virus long terminal repeat UAS. In addition, we studied multimers of several defined promoter elements (NFIL-2A, NF-kappa B, or NF-AT1) which are found in the UAS of the human IL-2 gene and which have been reported to be responsive to CsA when linked to a minimal promoter element (TATA box and transcription start site). Each promoter-regulatory region was fused to the bacterial chloramphenicol acetyltransferase gene and used to transiently transfect Jurkat cells. Quantitative chloramphenicol acetyltransferase assay determinations indicated that the transcriptional activity of each UAS induced upon T-cell activation was (i) completely sensitive, (ii) partially sensitive, or (iii) resistant to inhibition by CsA and FK-506. The induced transcription driven by the IL-2 promoter elements NF-AT1 and NFIL-2A could be blocked completely by FK-506 or CsA. Gel mobility shift assays indicated that the binding activities of the factors specifically interacting with these sequences were detected in activated cells regardless of whether the cells were treated with FK-506 or CsA. The results suggest that FK-506 or CsA inhibits a transacting mechanism(s) without disrupting the binding activities of these transcription factors. The degree to which each UAS was resistant to FK-506 was consistent with the level of transcription induced by phorbol myristate acetate, while UAS which were sensitive to inhibition by FK-506 were dependent on the presence of both phorbol myristate acetate and ionomycin.
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PMID:The immunosuppressant FK-506 specifically inhibits mitogen-induced activation of the interleukin-2 promoter and the isolated enhancer elements NFIL-2A and NF-AT1. 171 1

Ataxia-telangiectasia (A-T) is inherited as an monogenetic autosomal recessive disease. Ataxia appears around 1 year of age and progresses until the patient becomes wheelchair-bound, usually by age 10. This progress correlates with deterioration of Purkinje cells in the cerebellum. Sinopulmonary infections are common in patients from some countries but not others. One-third of the patients develop a neoplasm, usually lymphoid, sometime during their shortened lives. Conventional doses of radiation therapy for such cancers are contraindicated since A-T patients are hypersensitive to ionizing radiation. Five complementation groups have been described, based on correction of radioresistant DNA synthesis of fused fibroblasts from pairs of patients. Chromosomal translocations are found in 5-10% of peripheral T cells from most patients and the translocation breakpoints involve sites of normal somatic DNA rearrangement. Thus, the A-T gene(s) effects several cell lineages, suggesting that it is a "housekeeping" gene. Other speculations on "candidate genes" are considered. Recent progress localizing A-T to chromosome 11q23 is reviewed.
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PMID:Speculations on the ataxia-telangiectasia defect. 171 44

SV40-transformed ataxia-telangiectasia (AT) cells were transfected with a cosmid that contains a normal human DNA library and a selectable marker, the neo gene, which endows successfully transformed mammalian cells with resistance to the antibiotic G418. After a three-part selection protocol for G418 resistance and radioresistance, a cell line stably resistant to ionizing radiation was recovered. Cells from this line were irradiated with 50 Gy of X-rays and fused with non-transfected AT cells. Among the G418-resistant colonies recovered was one that was stably resistant to radiation. Resistance to ionizing radiation of both the primary transfectant line and its fusion derivative was intermediate between that of AT cells and normal cells, as assayed by colony-forming ability and measurement of radiation-induced G2 chromatid aberrations; both cell lines retained AT-like radioresistant DNA synthesis. These results suggest that, because radioresistance in the transfected cells was not as great as that in normal human cells, the two hallmarks of AT, radiosensitivity and radioresistant DNA synthesis, may still be the result of a single defective AT gene.
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PMID:Stable radioresistance in ataxia-telangiectasia cells containing DNA from normal human cells. 257 62

T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.
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PMID:The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis. 312 10

Fibroblast cultures from six unrelated patients having a familial type of immunodeficiency combined with microcephaly, developmental delay, and chromosomal instability were studied with respect to their response to ionizing radiation. The cells from five of them resembled those from individuals with ataxia telangiectasia (AT) in that they were two to three times more radiosensitive on the basis of clonogenic cell survival. In addition, after exposure to either X-rays or bleomycin, they showed an inhibition of DNA replication that was less pronounced than that in normal cells and characteristic of AT fibroblasts. However, the patients are clinically very different from AT patients, not showing any signs of neurocutaneous symptoms. Genetic complementation studies in fused cells, with the radioresistant DNA synthesis used as a marker, showed that the patients' cells could complement representatives of all presently known AT complementation groups. Furthermore, they were shown to constitute a genetically heterogeneous group as well. It is concluded that these patients are similar to AT patients with respect to cytological parameters. The clinical differences between these patients and AT patients are a reflection of genetic heterogeneity. The data indicate that the patients suffer from a chromosome-instability syndrome that is distinct from AT.
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PMID:Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia. 333 13

In a number of laboratories genetic analysis of ataxia-telangiectasia (AT) has been performed by studying the expression of the AT phenotype in fused somatic cells or mixtures of cell-free extracts from different patients. Complementation of the defective response to ionizing radiation was observed frequently, considering four different parameters for radiosensitivity in AT. The combined results from studies on cultured fibroblasts or lymphoblastoid cells from 17 unrelated families revealed the presence of at least four and possibly nine complementation groups. These findings suggest that there is an extensive genetic heterogeneity in AT. More extensive studies are needed for an integration of these data and to provide a set of genetically characterized cell strains for future research of the AT genetic defect.
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PMID:Complementation analysis of ataxia-telangiectasia. 386 36

The fibroblast cell line AT5BIVA, from ataxia telangiectasia complementation group D, was transfected with a neo gene providing G418 resistance for subsequent selections. The G418 resistant cell line was fused with gamma-irradiated Chinese hamster ovary cells and a radioresistant hybrid, atxbc, was isolated following an X-ray selection procedure. All the cellular defects characteristic of ataxia telangiectasia were corrected to some degree; atxbc cells: (i) were confirmed to be resistant to X-rays; (ii) had regained control over DNA synthesis after DNA damage, and (iii) could overcome the radiation-induced block in the G2 phase of the cell cycle. Repetitive element polymerase chain reaction amplification of integrated hamster DNA from primers to middle repetitive elements confirmed the presence of hamster-specific sequences, suggesting that the phenotype of the cells had been corrected by integration of a normal hamster gene rather than by a reversion event.
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PMID:Characterization of a hybrid hamster-human cell line complemented for the ataxia telangiectasia DNA repair defects. 794 20

Nitric oxide (NO) plays an important role not only in the regulation of blood vessel tone, but also in the growth of vascular smooth muscle cells (VSMC). The precise mechanism involved in the inhibition of VSMC growth by NO is not known. To further explore the effect of NO on VSMC growth, we examined the effect of NO on the expression of angiotensin II type 1 receptor (AT1-R) that is important for hypertrophy and hyperplasia of VSMC. S-nitroso acetyl DL-penicillamine (SNAP; 200 micromol/L), a potent NO donor, suppressed expression level of AT1-R mRNA by 90% and AT1-R number by 60% after 24 hours of stimulation. The suppressive effect was dose-dependent. Actinomycin D, which is an inhibitor of gene transcription, did not affect the decrease of AT1-R mRNA by NO. Cyclic guanosine monophosphate (cGMP) analogue, 8 bromo-cGMP, did not affect AT1-R mRNA level. Deletion mutants of the promoter region of rat AT1a-R gene were fused to luciferase reporter gene and introduced to VSMC. Transfected cells were stimulated with SNAP, and luciferase activity was measured. Inhibitory effect of NO was still observed in the shortest deletion mutant that contained 61 bp upstream from transcription start site. In this DNA segment, two DNA binding protein were observed by gel mobility shift assay, and one of these binding proteins was decreased on stimulation by NO. NO downregulates AT1-R gene expression independently of cGMP. A DNA binding protein that binds to the proximal promoter region of AT1-R gene may be responsible for this inhibitory effect. The inhibition of AT1-R gene expression may be implicated in the anti-atherogenic property of NO.
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PMID:Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide. 945 26

Angiotensin II (Ang II) receptors of the AT1 subtype are coupled to heterotrimeric G nucleotide-binding proteins, G(q/11), to activate phospholipase C-beta isoforms with production of inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol. The resultant release of intracellular Ca2+ and increased Ca2+ influx are major determinants of several acute cellular responses initiated by Ang II, including secretion of aldosterone from the adrenal cortex and smooth muscle contraction. However, cellular events related to more prolonged effects of Ang II, such as hypertrophic and hyperplastic responses, are triggered by intracellular signaling cascades that are less dependent on Ca2+ signals. The Ang II-induced activation of Raf-1 kinase, p42 MAP-kinase and c-fos expression in response to Ang II in adrenal glomerulosa cells does not require Ca2+ influx. Moreover, the dose-response relationships for Raf-1 activation, MAP-kinase activation and mitogenesis show significantly higher sensitivity to Ang II than the InsP3, Ca2+-release and aldosterone secretory responses. The sensitivities of both Raf-1 kinase and MAP-kinase stimulation by Ang II to the inhibitors of phosphoinositide kinases, wortmannin and LY 294002, suggest that inositol phospholipids may play a role in these activation events unrelated to their role in Ca2+ signaling. To investigate the changes of various inositides after stimulation at the single cell level, fluorescent probes were developed in which pleckstrin homology domains with distinct binding specificities to inositol phospholipids were fused to the green fluorescent protein and expressed in NIH 3T3 cells. The use of these probes revealed heterogeneity of the inositol lipid pools and their complex relationship to Ca2+ signals. The use of these tools will help to further clarify the complex role of these lipids in initiating Ca2+-dependent and -independent signaling responses.
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PMID:Signaling events activated by angiotensin II receptors: what goes before and after the calcium signals. 988 5

Growth factors and agonists of both G alpha s and G alpha q-coupled receptor agonists each down regulate angiotensin AT1 receptor gene expression in vascular smooth muscle cells. To test whether the transcription factor CREB is in the pathway involved in modulation of AT1-receptor gene expression, AT1 receptor mRNA levels were measured after stimulation with forskolin, angiotensin II and PDGF-BB in VSMC expressing the inducible cAMP early repressor protein, ICERIIgamma, fused to the green fluorescent protein (eGFP). This fusion protein inhibits luciferase induction from promoters driven by either CREB response elements (CRE) or, unexpectedly, by tetradecanoylphorbol acetate response elements (TRE), which bind activator protein (AP-1). EGFP-ICERIIgamma expression inhibits occupancy of CRE and TRE elements by endogenous VSMC nuclear proteins. Nevertheless, agonist-induced AT1-receptor mRNA down regulation is unaffected by eGFP-ICERIIgamma expression. Although CREB transcription is activated by multiple classes of agonists in VSMC, and ICER can inhibit agonist-induced transcription mediated by both CREB and AP-1 enhancers, these transcription factors are not obligate components of the pathways regulating AT1-R gene expression in rat VSMC.
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PMID:The inducible cAMP early repressor ICERIIgamma inhibits CREB and AP-1 transcription but not AT1 receptor gene expression in vascular smooth muscle cells. 1110 42


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