Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional process that amplifies the repertoire of protein production. Recently, the induction of this process through up-regulation of the editing enzyme RNA-specific adenosine deaminase 1 (ADAR1) was documented during acute inflammation. Here we report that the inflammation-induced up-regulation of ADAR1 involves differential production and intracellular localization of several isoforms with distinct RNA-binding domains and localization signals. These include the full-length ADAR1 (p150) and two functionally active short isoforms (p80 and p110). ADAR1 p80 starts at a methionine 519 (M519) due to alternative splicing in exon 2, which deletes the putative nuclear localization signal, the Z-DNA binding domain, and the entire RNA binding domain I. ADAR1 p110 is the mouse homologue of the human ADAR1 110-kDa variant (M246), which retains the second half of the Z-DNA binding domain, all RNA binding domains, and the deaminase domain. Additional variations are found in the third RNA binding domain of ADAR1; they are differentially regulated during inflammation, generating isoforms with different levels of activities. Studies in several cell types transfected with ADAR1-EGFP chimeras demonstrated that the p150 and p80 variants are localized in the cytoplasm and nucleolus, respectively. In agreement with this observation, endogenous ADAR1 was identified in the cytoplasm and nucleolus of mouse splenocytes and HeLa cells. Since the ADAR1 variants are differentially regulated during acute inflammation, it suggests that the localization of these variants and of A-to-I RNA editing in the cytoplasm, nucleus, and nucleolus is intracellularly reorganized in response to inflammatory stimulation.
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PMID:Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation. 1295 22

ADAR1 (adenosine deaminase acting on RNA) is widely expressed in adult mammals and has a critical role during embryogenesis. Two size forms of ADAR1 are known that possess adenosine-to-inosine editing activity: an interferon (IFN)-inducible approximately 150-kDa protein and a constitutively expressed N-terminally truncated approximately 110-kDa protein. We defined the structure of the 5'-flanking region of the mouse Adar1 gene, and we show here that mouse Adar1 transcripts possess alternative exon 1 structures (1A, 1B, and 1C) that initiate from unique promoters and are spliced to a common exon 2 junction. Exon 1A-containing transcripts encoding p150 were expressed in all tissues examined from adult mice (brain, cecum, heart, kidney, liver, lung, spleen, and Peyer's patches) and were elevated most significantly in liver but remained lowest in brain following oral infection with Salmonella. Exon 1B-containing RNA was most abundant in brain and was not increased in any tissue examined following infection. Exon 1C-containing RNA was very scarce. Exon 1A, but not exon 1B or 1C, expression was increased in fibroblast L cells treated with IFN, and a consensus ISRE element was present in the promoter driving exon 1A expression. Exon 1B, but not 1A, was detectable in embryonic day 10.5 embryos and was abundantly expressed in embryonic day 15 embryos. Furthermore, the ADAR1 p110 protein isoform was detected in embryonic tissue, whereas both p110 and the inducible p150 proteins were found in IFN-treated L cells. Finally, the presence of alternative exon 7a correlated with exon 1B-containing RNA, and alternative exon 7b correlated with exon 1A-containing RNA. These results establish that multiple promoters drive the expression of the Adar1 gene in adult mice, that the IFN inducible promoter and exon 1A-containing RNA are primarily responsible for the increased ADAR1 observed in Salmonella-infected mice, and that the constitutive exon 1B-containing transcript and encoded p110 protein product are abundantly expressed both in adult brain and during embryogenesis.
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PMID:Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. 1567 78

Previous studies showed adenosine deaminase that acts on RNA (ADAR1) up-regulated in alveolar macrophages (AMs) by LPS treatment, whereas its roles in acute lung injury (ALI) are still unclear. Here, we report that up-regulation of inducible ADAR1 p150 isoform in macrophages stimulated with LPS and in AMs harvested from an ALI rat model. Knockdown of ADAR1 p150 by small interfering RNA in AMs suppressed macrophage inflammatory protein 1 (MIP-1) secretion while enhancing that of IL-10 compared with those control cells upon LPS stimulation. To further confirm the role of p150 in AMs, adoptive transfer of LPS-activated NR8383 cells was performed in healthy rats, and severity of inflammatory response was assessed by investigating cellular pattern in bronchoalveolar lavage fluid and calculating alveolar-arterial oxygen difference [D(A-a)O2]. Acute lung injury was induced by LPS-activated NR8383 cells with either normal or lower ADAR1 expression levels, and ALI in rats and the lung inflammation was attenuated significantly by knockdown ADAR1 p150 in transferred cells both in polymorphonuclear leukocyte infiltration and D(A-a)O2. The roles of MIP-1 and IL-10 in the development of ALI were also tested in animals receiving neutralizing antibodies. Administration of anti-MIP-1 inhibited lung polymorphonuclear leukocytes infiltration and lung damage, as well as D(A-a)O2, whereas anti-IL-10 reversed the protection effects. In conclusion, ADAR1 p150 is functionally significant in the development of ALI. It likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment and D(A-a)O2. It also implied that ADAR1 inhibitors may help attenuate local inflammatory lung damage.
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PMID:Adenosine deaminase that acts on RNA 1 p150 in alveolar macrophage is involved in LPS-induced lung injury. 1852 Jul 2

The p150 form of the RNA-specific adenosine deaminase ADAR1 is interferon-inducible and catalyzes A-to-I editing of viral and cellular RNAs. We have characterized mouse genomic clones containing the promoter regions required for Adar1 gene transcription and analyzed interferon induction of the p150 protein using mutant mouse cell lines. Transient transfection analyses using reporter constructs led to the identification of three promoters, one interferon-inducible (P(A)) and two constitutively active (P(B) and P(C)). The TATA-less P(A) promoter, characterized by the presence of a consensus ISRE element and a PKR kinase KCS-like element, directed interferon-inducible reporter expression in rodent and human cells. Interferon induction of p150 was impaired in mouse cells deficient in IFNAR receptor, JAK1 kinase or STAT2 but not STAT1. Whereas Adar1 gene organization involving multiple promoters and alternative exon 1 structures was highly preserved, sequences of the promoters and exon 1 structures were not well conserved between human and mouse.
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PMID:Organization of the mouse RNA-specific adenosine deaminase Adar1 gene 5'-region and demonstration of STAT1-independent, STAT2-dependent transcriptional activation by interferon. 1877 82

The interferon-induced protein kinase RNA activated (PKR) is activated after virus infection. This activation is transient during the human immunodeficiency virus type 1 (HIV-1) infection of lymphocytes, and the protein is not activated at the peak of infection. We observed that interferon-induced adenosine deaminase acting on RNA 1-p150 (ADAR1-p150) and ADAR1-p110 expression increases while the virus replicates actively. Furthermore, both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. We observed that ADAR1-p150, as previously shown for the TAR RNA binding protein (TRBP), reverses the PKR inhibition of HIV expression and production in HEK 293T cells. This activity requires the Z-DNA binding motif and the three double-stranded RNA binding domains but not the catalytic domain. In astrocytic cells, ADAR1-p150 increased HIV expression and production to an extent similar to that of TRBP. Small interfering RNAs against ADAR1-p150 moderately decreased HIV production. These results indicate that two interferon-induced proteins, ADAR1 and PKR, have antagonistic functions on HIV production. They suggest that ADAR1 and TRBP belong to a multiprotein complex that inhibits PKR during the HIV infection of lymphocytes.
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PMID:ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. 1960 74

ADAR1 (adenosine deaminase acting on RNA) catalyzes the conversion of adenosine to inosine, a process known as A-to-I editing. Extensive A-to-I editing has been described in viral RNAs isolated from the brains of patients persistently infected with measles virus, although the precise role of ADAR during measles virus infection remains unknown. We generated human HeLa cells stably deficient in ADAR1 ("ADAR1(kd) cells") through short hairpin RNA-mediated knockdown, and using these cells, we tested the effect of ADAR1 deficiency on measles virus (MVvac strain) growth and virus-induced cell death. We found that the growth of mutant viruses lacking expression of the viral accessory proteins V and C (V(ko) and C(ko), respectively) was decreased in ADAR1-deficient cells compared with ADAR1-sufficient cells. In addition, apoptosis was enhanced in ADAR1-deficient cells following infection with wild type and V(ko) virus but not following infection with C(ko) virus or treatment with tumor necrosis factor-alpha or staurosporine. Furthermore, in C(ko)-infected ADAR1-sufficient cells when ADAR1 did not protect against apoptosis, caspase cleavage of the ADAR1 p150 protein was detected. Finally, enhanced apoptosis in ADAR1(kd) cells following infection with wild type and V(ko) virus correlated with enhanced activation of PKR kinase and interferon regulatory factor IRF-3. Taken together, these results demonstrate that ADAR1 is a proviral, antiapoptotic host factor in the context of measles virus infection and suggest that the antiapoptotic activity of ADAR1 is achieved through suppression of activation of proapoptotic and double-stranded RNA-dependent activities, as exemplified by PKR and IRF-3.
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PMID:RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. 1971 21

ADAR1 (adenosine deaminase acting on RNA) catalyzes the deamination of adenosine to inosine on RNA substrates with double-stranded character. Here, we show that coexpression of ADAR1 in mammalian cells markedly increases plasmid-based gene expression in transfected cells. The enhanced expression was independent of the nature of the promoter (viral and cellular) used to drive gene expression, of the protein reporter (luciferase and RRP) tested, and of the human cell line examined (293T and HeLa). Exogenous protein levels were increased by approximately 20-fold to approximately 50-fold when ADAR1 was coexpressed, whereas RNA transcript levels changed by less than 2-fold. The activation of PKR (protein kinase regulated by RNA) protein kinase and the phosphorylation of translation initiation factor eIF-2alpha seen following plasmid DNA transfection were both greatly reduced in ADAR1-transfected cells. Stable knockdown of the PKR kinase increased reporter gene expression in the absence, but not in the presence, of ADAR1 coexpression. Both size forms of ADAR1-the p150-inducible form and the p110-like constitutive form-enhanced plasmid-based gene expression. Taken together, these results indicate that the ADAR1 deaminase increases exogenous gene expression at the translational level by decreasing PKR-dependent eIF-2alpha phosphorylation.
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PMID:Adenosine deaminase ADAR1 increases gene expression at the translational level by decreasing protein kinase PKR-dependent eIF-2alpha phosphorylation. 1973 81

Two size forms of ADAR1 adenosine deaminase are known, one constitutively expressed (p110) and the other interferon (IFN)-induced (p150). To test the role of ADAR1 in viral infection, HeLa cells with ADAR1 stably knocked down and 293 cells overexpressing ADAR1 were utilized. Overexpression of p150 ADAR1 had no significant effect on the yield of vesicular stomatitis virus. Likewise, reduction of p110 and p150 ADAR1 proteins to less than approximately 10 to 15% of parental levels (ADAR1-deficient) had no significant effect on VSV growth in the absence of IFN treatment. However, inhibition of virus growth following IFN treatment was approximately 1 log(10) further reduced compared to ADAR1-sufficient cells. The level of phosphorylated protein kinase PKR was increased in ADAR1-deficient cells compared to ADAR1-sufficient cells following IFN treatment, regardless of viral infection. These results suggest that ADAR1 suppresses activation of PKR and inhibition of VSV growth in response to IFN treatment.
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PMID:RNA adenosine deaminase ADAR1 deficiency leads to increased activation of protein kinase PKR and reduced vesicular stomatitis virus growth following interferon treatment. 1991 73

Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150(-/-) but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150(-/-) cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150(-/-) cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses.
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PMID:RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. 2159 18

The posttranscriptional RNA editing by the type 1 adenosine deaminase acting on RNAs (ADAR1), expressed as p110 and p150 isoforms, is important for both physiological and pathological processes. Their expression and significance in leukemias remain unknown. Here, we investigated the expression of ADAR1 in Chinese pediatric acute leukemias by real-time PCR and Western blot. The results showed that significant high expression of p110 was detected in leukemias, especially in B-ALL, whereas a slight increase of p150 could be observed. Furthermore, the decrease of p110 expression was observed in B-ALL patients achieving complete remission. Moreover, among prognostic risk groups in ALL, the highest expressions of p110 and p150 were detected in standard-risk group, whereas their lowest expressions were in high-risk group. This observation was further confirmed in comparisons between good and poor prognostic groups based on prognostic related clinical features. These results demonstrated that ADAR1 isoforms showed different expression patterns, suggesting that they might play different roles in pediatric leukemias. Our results will help us for the better understanding of RNA editing, exploring the potential target for the treatment, and making prognostic evaluation in childhood leukemias.
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PMID:Abnormal expression of ADAR1 isoforms in Chinese pediatric acute leukemias. 2131 40


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