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: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is widely accepted that fatty acid amide hydrolase (FAAH) plays a central role in the hydrolysis of anandamide. However, we found a second N-acylethanolamine hydrolase in animal tissues which hydrolyzed anandamide at acidic pH. This "acid amidase" was first detected with the particulate fraction of human megakaryoblastic CMK cells, and was solubilized by freezing and thawing without detergent. The enzyme was distinguishable from FAAH in terms of (1) the optimal activity at pH 5, (2) stimulation by dithiothreitol, (3) low sensitivity to two FAAH inhibitors (methyl arachidonyl fluorophosphonate and phenylmethylsulfonyl fluoride), and (4) high content in lung, spleen and macrophages of rat. The acid amidase purified from rat lung was the most active with N-palmitoylethanolamine among various long-chain N-acylethanolamines. To develop specific inhibitors for this enzyme, we screened various analogues of N-palmitoylethanolamine. Among the tested compounds, N-cyclohexanecarbonylpentadecylamine was the most potent inhibitor which does-dependently inhibited the enzyme with an IC(50) value of 4.5 microM without inhibiting FAAH at concentrations up to 100 microM. The inhibitor was a useful tool to distinguish the acid amidase from FAAH with rat basophilic leukemia (RBL-1) cells that express both the enzymes.
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PMID:A second N-acylethanolamine hydrolase in mammalian tissues. 1591 Aug 84

Mutations in transcription factors constitute one means by which normal hematopoietic progenitors are converted to leukemic stem cells. Recently, acquired mutations in the megakaryocytic regulator GATA1 have been found in essentially all cases of acute megakaryoblastic leukemia (AMkL) in children with Down syndrome and in the closely related malignancy transient myeloproliferative disorder. In all cases, mutations in GATA1 lead to the expression of a shorter isoform of GATA-1, named GATA-1s. Because GATA-1s retains both DNA binding zinc fingers, but is missing the N-terminal transactivation domain, it has been predicted that the inability of GATA-1s to regulate its normal class of megakaryocytic target genes is the mechanism by which mutations in GATA1 contribute to the disease. Indeed, several recent reports have confirmed that GATA-1s fails to properly regulate the growth of megakaryocytic precursors, likely through aberrant transcriptional regulation. Although the specific target genes of GATA-1 mis-regulated by GATA-1s that drive this abnormal growth remain undefined, multiple candidate genes have been identified via gene array studies. Finally, the inability of GATA-1s to promote expression of important metabolic genes, such as cytadine deaminase, likely contributes to the remarkable hypersensitivity of AMkL blasts to cytosine arabinoside. Future studies to define the entire class of genes dysregulated by mutations in GATA1 will provide important insights into the etiology of these malignancies.
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PMID:Transcription factor GATA-1 and Down syndrome leukemogenesis. 1684 Jan 87

Immunoglobulins (Igs) or antibodies (Abs) are the principal operators of the adaptive humoral immune response. For optimum functional activity they acquire an optimized structure for antigen (Ag) recognition, precipitation, agglutination, phagocytosis (IgG1/3 and IgA), cytotoxicity (IgG1/3), transport through mucosa (IgA and IgM) and placenta (IgG1/3), complement activation (IgG1/3 and IgM) and release of inflammatory mediators (IgE). A diversity with potentially up to 10(15) different Ab specificities is generated during Ag-independent B cell development in the bone marrow by combinatorial V-D-J joining, creation of junctional diversity, and combinatorial association of L and H chains. Furthermore,Ab variety is created during Ag-dependent B cell maturation in peripheral lymphatic tissues by isotype class switching and somatic hypermutation. Two types of enzymes play a key role in Ab diverseness, i. e., the products of recombination-activating genes RAG1 and RAG2 and the affinity induced deaminase (AID). The prevailing adult-type B2 cells provide the basis for the acquired humoral immune response characterized by Ab production,Ag processing and presentation, immunological memory and tolerance along with the generation of the anti-idiotype network,whereas the fetal-type B1 cells may play a role in innate immunity and autoimmunity. Impairment of B cell immunity includes immunodeficiency (agammaglobulinemia), malignant transformation (leukemia, lymphoma, plasmocytoma) and immune dysregulation (allergy, autoimmunity). The diagnostic relevance of Abs comprises classical serology (immunoprecipitation, agglutination, complement binding, RIA, ELISA), immunocytochemistry and immunohistochemistry, immunofluorescence (microscopic and flow cytometric), cytotoxicity tests, immunoblots, immunospot assays and immunoabsorption (affinity chromatography). Therapeutic application of Abs (passive immunization) is directed against infections, intoxications, solid tumors, leukemias and lymphomas, graft rejection and graft-versus-host reaction, hemolytic anemia, and autoimmune diseases. The generation of genetically engineered monoclonal Abs (mAbs) has revolutionized the diagnostic and therapeutic potential of Abs in almost all disciplines of modern medicine.
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PMID:Immunoglobulins--basic considerations. 1699 62

Approximately 17% of the human genome is comprised of long interspersed nuclear element 1 (LINE-1, L1) non-LTR retrotransposons. L1 retrotransposition is known to be the cause of several genetic diseases, such as hemophilia A, Duchene muscular dystrophy, and so on. The L1 retroelements are also able to cause colon cancer, suggesting that L1 transposition could occur not only in germ cells, but also in somatic cells if innate immunity would not function appropriately. The mechanisms of L1 transposition restriction in the normal cells, however, are not fully defined. We here show that antiretroviral innate proteins, human APOBEC3 (hA3) family members, from hA3A to hA3H, differentially reduce the level of L1 retrotransposition that does not correlate either with antiviral activity against Vif-deficient HIV-1 and murine leukemia virus, or with patterns of subcellular localization. Importantly, hA3G protein inhibits L1 retrotransposition, in striking contrast to the recent reports. Inhibitory effect of hA3 family members on L1 transposition might not be due to deaminase activity, but due to novel mechanism(s). Thus, we conclude that all hA3 proteins act to differentially suppress uncontrolled transposition of L1 elements.
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PMID:All APOBEC3 family proteins differentially inhibit LINE-1 retrotransposition. 1743 59

Apobec proteins are a family of cellular cytidine deaminases, among which several members have been shown to have potent antiviral properties. This antiviral activity is associated with the ability to cause hypermutation of retroviral cDNA. However, recent research has indicated that Apobec proteins are also able to inhibit retroviruses by other mechanisms that are independent of their deaminase activity. We have compared the antiviral activities of human and murine Apobec3 (A3) proteins, and we have found that, consistent with previous reports, human immunodeficiency virus (HIV) is able to resist human A3G but is sensitive to murine A3, whereas murine leukemia virus (MLV) is relatively resistant to murine A3 (mA3) but sensitive to human A3G. In contrast to previous studies, we observed that mA3 is packaged efficiently into MLV particles. The C-terminal cytidine deaminase domain (CDD2) is required for packaging of mA3 into MLV particles, and packaging did not depend on the MLV viral RNA. However, mA3 packed into MLV particles failed to cause hypermutation of viral DNA, indicating that its deaminase activity is blocked or inhibited. hA3G also caused significantly less hypermutation of MLV than of HIV DNA. Both mA3 and the splice variant mA3Delta5 exhibited some residual antiviral activity against MLV and caused a reduction in the ability of MLV particles to generate reverse transcription products. These results suggest that MLV has evolved specific mechanisms to block the ability of Apobec proteins to mediate deaminase-dependent hypermutation.
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PMID:Species-specific restriction of apobec3-mediated hypermutation. 1803 89

APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G) was identified as an anti-HIV-1 (human immunodeficiency virus type 1) cellular factor in target CD4 T cells. It is a member of the APOBEC family of cytidine deaminases consisting of APOBEC1, APOBEC2, APOBEC3 (A to H), and AID (activation induced deaminase). During reverse transcription, it deaminates dC to dU in nascent minus-strand viral DNA, resulting in G-to-A hypermutation in the plus strand DNA to inhibit the replication of HIV-1. On the contrary, HIV-1 Vif protein counteracts this enzyme by the ubiquitin-proteasome pathway to enable HIV-1 replicate in target cells. Vif forms an E3 ligase complex with cellular proteins including Cullin5, ElonginB, and ElonginC (Vif-BC-Cul5) and functions as a substrate recognition subunit of the complex to target APOBEC3G for ubiquitin-proteasome dependent degradation in virus-producing cells. APOBEC3G has also been shown to have a broad antiviral activity on a wide variety of viruses which include not only retroviruses such as other lentiviruses, murine leukemia virus (MLV), and human T-cell leukemia virus type 1 (HTLV-1) but also other viruses such as hepatitis B virus (HBV) and adeno-associated virus. Furthermore, other members of the APOBEC family also show a broad antiviral activity, but target virus specificities vary among APOBEC members. On the other hand, viruses have their own mechanisms to escape from APOBEC. These expanding evidences suggest that the APOBEC family of cytidine deaminases plays an important role in antiviral innate immunity and might be a novel target for an antiviral therapy. Here we review the present understanding of APOBEC3 proteins as an antiviral innate immunity and battles between APOBEC3 and viruses.
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PMID:Cytidine deaminases as a weapon against retroviruses and a new target for antiviral therapy. 1833 43

Cytidine (CR) deaminase is a key enzyme in the catabolism of cytosine nucleoside analogues, since their deamination results in a loss of their pharmacological activity. In this report we have investigated the importance of CR deaminase with respect to the antineoplastic action of inhibitors of DNA methylation, 5-aza-2'-deoxycytidine (5-AZA-CdR) and zebularine. Zebularine has a dual mechanism of action, since it can also inhibit CR deaminase. The objective of our study was to investigate the importance of zebularine as an inhibitor of CR deaminase with respect to the antineoplastic action of 5-AZA-CdR. Using an in vitro clonogenic assay, we investigated the antineoplastic action of 5-AZA-CdR and zebularine, alone and in combination on wild type 3T3 murine fibroblasts and corresponding V5 cells transduced with CR deaminase gene to express a very high level of CR deaminase activity. The V5 cells were much less sensitive to 5-AZA-CdR than the wild type 3T3 cells. The addition of zebularine significantly enhanced the antineoplastic action of 5-AZA-CdR on V5 cells, but not 3T3 cells. Enzymatic analysis on CR deaminase purified from the V5 cells showed that zebularine is a competitive inhibitor of the deamination of 5-AZA-CdR. These in vitro observations are in accord with our in vivo study in mice with L1210 leukemia, which showed that zebularine increased the antileukemic activity of 5-AZA-CdR. Pharmacokinetic analysis also showed that zebularine increased the plasma level of 5-AZA-CdR during an i.v. infusion in mice. Our results indicate that the major mechanism by which zebularine enhances the antineoplastic action of 5-AZA-CdR is by inhibition of CR deaminase. These findings provide a rationale to investigate 5-AZA-CdR in combination with zebularine in patients with advanced leukemia.
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PMID:Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2'-deoxycytidine. 1839 9

The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.
Leukemia 2010 Jan
PMID:Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients. 1975 60

Mouse APOBEC3 (mA3) is a cytidine deaminase with antiviral activity. mA3 is linked to the Rfv3 virus resistance factor, a gene responsible for recovery from infection by Friend murine leukemia virus, and mA3 allelic variants differ in their ability to restrict mouse mammary tumor virus. We sequenced mA3 genes from 38 inbred strains and wild mouse species, and compared the mouse sequence and predicted structure with human APOBEC3G (hA3G). An inserted sequence was identified in the virus restrictive C57BL strain allele that disrupts a splice donor site. This insertion represents the long terminal repeat of the xenotropic mouse gammaretrovirus, and was acquired in Eurasian mice that harbor xenotropic retrovirus. This viral regulatory sequence does not alter splicing but is associated with elevated mA3 expression levels in spleens of laboratory and wild-derived mice. Analysis of Mus mA3 coding sequences produced evidence of positive selection and identified 10 codons with very high posterior probabilities of having evolved under positive selection. Six of these codons lie in two clusters in the N-terminal catalytically active cytidine deaminase domain (CDA), and 5 of those 6 codons are polymorphic in Rfv3 virus restrictive and nonrestrictive mice and align with hA3G CDA codons that are critical for deaminase activity. Homology models of mA3 indicate that the two selected codon clusters specify residues that are opposite each other along the predicted CDA active site groove, and that one cluster corresponds to an hAPOBEC substrate recognition loop. Substitutions at these clustered mA3 codons alter antiviral activity. This analysis suggests that mA3 has been under positive selection throughout Mus evolution, and identified an inserted retroviral regulatory sequence associated with enhanced expression in virus resistant mice and specific residues that modulate antiviral activity.
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PMID:Adaptive evolution of Mus Apobec3 includes retroviral insertion and positive selection at two clusters of residues flanking the substrate groove. 2061 65

The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including murine leukemia virus and human immunodeficiency virus (HIV)-1, is now well established. The RNA editing family member apolipoprotein B (apo B)-editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C-U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but its activity against endogenous retroelements remains unclear. Here, we show in cell culture-based retrotransposition assays that A1 family proteins from multiple mammalian species can also reduce the mobility and infectivity potential of LINE-1 (long interspersed nucleotide sequence-1, L1) and long-terminal repeats (LTRs) retrotransposons (or endogenous retroviruses), such as murine intracisternal A-particle (IAP) and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism, and was not affected by subcellular localization of the proteins. In contrast, the inhibition of LTR-retrotransposons appeared to require the deaminase activity of A1 proteins. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in several mammalian species.
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PMID:Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons. 2139 38


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