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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the interleukin-2 receptor alpha-(IL-2Ralpha-), IL-2Rbeta-, and the recently identified IL-2Rgamma-chain was examined on a wide range of cells of myeloid origin including neutrophils, monocytes, normal bone marrow-derived myeloid progenitors enriched for CD34+ cells, bone marrow blasts obtained from acute myelogenous leukemia (AML) patients, and permanent myeloid leukemia cell lines by reverse transcriptase-polymerase chain reaction and surface membrane analysis using receptor chain-specific monoclonal antibodies and flow cytometry. Expression of the p75 IL-2Rbeta- and the p64 IL-2Rgamma-chain was a common finding in most of the myeloid cell samples investigated, whereas IL-2Ralpha-chain was less frequently expressed. Although the high-affinity IL-2R form (ie, the alpha+, beta+, gamma+ IL-2R form) was detectable in a small minority of primary AML samples as well as the KG-1 cell line and IL-2 binding to these cells was sufficient to initiate signal transduction as evidenced by an increase in overall protein tyrosine phosphorylation and more specifically in tyrosine phosphorylation of the Janus kinase (JAK) 3, in none of these cell types did exposure to IL-2 affect cell growth kinetics. These results suggest that, in myeloid cells, the IL-2R may not stimulate mitogenic responses or that its components may be expressed in a combinational association with receptors for other cytokines and that IL-2Rgamma may play a regulatory role in normal and malignant myelopoiesis possibly independent from IL-2. Because recent studies by others have indicated that the IL-2Rgamma- chain may be shared by the IL-4R, the IL-7R, and most likely the IL-9R, expression of mRNA of these receptor types was also investigated in these cell samples. Surprisingly, in a substantial part of the myeloid lineage cells examined, an IL-2Rgamma+, IL-4R-, IL7R- configuration was noted that was, however, frequently associated with expression of IL-9R. Sharing of IL-9R/IL-2R components was furthermore suggested by inhibition of 125I-IL-2 binding to primary AML cells with excess of unlabeled IL-9.
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PMID:Transcript synthesis and surface expression of the interleukin-2 receptor (alpha-, beta-, and gamma-chain) by normal and malignant myeloid cells. 863 Apr 6

Human parotid tumors were evaluated for the activation of the phosphotyrosine signaling pathway by Western blot, enzyme activity assay, and reverse transcriptase-polymerase chain reaction. Warthin's tumor and mucoepidermoid carcinomas had the greatest level of tyrosine phosphorylated proteins identified in plasma membrane fractions. These tumors, along with pleomorphic adenocarcinoma, showed high levels of membrane expression of the tyrosine kinase receptor, c-erbB-2, and phosphatidylinositol-3-kinase. Expression of the epidermal growth factor receptor was confined to normal tissue. The level of mRNA for c-erb was elevated only in mucoepidermoid carcinomas. Messenger RNA levels for ras were unchanged from control levels in all tumors, while the level of src mRNA was higher in the tumor samples than the normal parotid tissue. The activities of several signal transduction kinases, including protein kinase A and C were elevated in tumor tissue (7.7- to 18.9- and 0.4- to 3.7-fold higher, respectively), relative to surrounding normal tissue. While the level of glandular amylase was reduced (22%-0% of normal levels) in the tumor tissue, epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) content was dramatically higher in the neoplastic tissue (10- to 170-fold and 4.6- to 6.0-fold, respectively). These results suggest that with the presence of elevated levels of EGF, TGFalpha, and the oncoprotein receptor c-erbB-2 in the membrane of parotid tumors, cell proliferation and activation of the phosphotyrosine signal transduction pathway may involve autocrine stimulation through the expression of high levels of growth factor and receptor in the same tissue.
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PMID:Alterations in the level of phosphotyrosine signal transduction constituents in human parotid tumors. 863 6

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.
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PMID:(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes. 864 4

Tyrosine kinases play central roles in the growth and differentiation of normal and tumor cells. In this study, we have analyzed the general tyrosine kinase expression profile of a prostate carcinoma (PCA) xenograft, CWR22. We describe here an improved reverse transcriptase-PCR approach that permits identification of nearly 40 different kinases in a single screening; several of these kinases are newly cloned kinases and some are novel. According to this, there are 11 receptor kinases, 9 nonreceptor kinases, and at least 7 dual kinases expressed in the xenograft tissue. The receptor kinases include erbB2, erbB3, Ret, platelet-derived growth factor receptor, sky, nyk, eph, htk, sek (eph), ddr, and tkt. The nonreceptor kinases are lck, yes, abl, arg, JakI, tyk2, and etk/bmx. Most of the dual kinases are in the mitogen-activating protein (MAP) kinase-kinase (MKK) family, which includes MKK3, MKK4, MEK5, and a novel one. As a complementary approach, we also analyzed by specific reverse transcriptase-PCR primers the expression profile of erbB/epidermal growth factor receptor family receptors in a variety of PCA specimens, cell lines, and benign prostatic hyperplasia. We found that erbB1, -2, and -3 are often coexpressed in prostate tissues, but not in erbB4. The information established here should provide a base line to study the possible growth and oncogenic signals of PCA.
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PMID:A tyrosine kinase profile of prostate carcinoma. 865 Feb 1

A cDNA encoding the mouse delta opioid receptor was expressed stably in a Rat 1 fibroblast cell line. Expression of this receptor was demonstrated both in ligand binding studies and by reverse transcriptase-PCR. In membranes of clone D2 cells the opioid peptide [D-Ala(2)]-leucine enkephalin (DADLE) produced a robust, concentration-dependent, stimulation of basal high-affinity GTPase activity; the prototypic opioid antagonist naloxone and the highly selective and potent delta opioid ligands H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic[Ch2-NH]Phe-Phe-OH (TIPP[psi]) had little effect but N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI174864) caused a marked dose-dependent inhibition of this activity (Tic, 1,2,3,4-tetrahydroisoquinolin-2-yl-carbonyl]; Aib, alpha-aminobutyric acid). This effect of ICI174864 was reversed by TIPP[psi] and attenuated after treatment of the cells with pertussis toxin. No stimulation by DADLE or inhibition by ICI174864 was observed in Rat 1 fibroblasts that did not express the delta opioid receptor. Basal binding of [(35)S]guanosine 5'-O-(3-thio-triphosphate) to membranes of clone D2 cells was also stimulated by DADLE and inhibited by ICI174864; both of these effects were reversed by co-incubation with TIPP[psi]. When cholera toxin-catalysed [(32)P]ADP-ribosylation was performed on membranes of clone D2 cells in the absence of guanine nucleotides, a 40 kDa G1-family polypeptide was labelled in addition to both the long and short isoforms of Gsalpha. Labelling of the 40 kDa polypeptide was enhanced by addition of DADLE and fully attenuated by addition of ICI174864. In contrast, labelling of the isoforms of Gsalpha was unaffected by either opioid ligand. Again, both the positive effect of DADLE and the inhibitory effect of ICI174864 were prevented by co-incubation with TIPP[psi] which, in isolation, had little effect on cholera toxin-catalysed [(32)P]ADP-ribosylation of either Gs or Gi. These data demonstrate that the delta opioid receptor displays a spontaneous activity when expressed in this genetic background. Attenuation of this activity is produced by ICI174864, which by acting as an 'inverse agonist' in this system, functionally uncouples the expressed receptor from the cellular G-protein population. The complete attenuation of agonist-independent cholera toxin-catalysed [(32)P]ADP-ribosylation of Gi demonstrated that ICI174864 acts as an inverse agonist with high intrinsic activity at this receptor.
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PMID:Analysis of inverse agonism at the delta opioid receptor after expression in Rat 1 fibroblasts. 867 Jan 11

Among human immunodeficiency type 1 viruses (HIV-1) isolated during long-term 3'-azido-3'-deoxythymidine (AZT) therapy, 4 condoms (Asp67, Lys70, Thr215, and Lys219) in the HIV-1-reverse transcriptase (RT)-coding region have been considered to be related to the AZT resistance of HIV-1. Therefore we determined these mutation patterns in HIV-1 isolates from patients undergoing long-term AZT treatment. In 41 clones of HIV-1 from 7 patients, the Thr215 mutation was the most predominant (97.6%), and more frequent than Asp67 (48.8%), Lys70 (31.7%) and Lys219 (9.8%) mutations. All 22 clones from isolates cultured in the presence of 1 microM AZT Thr215 mutation; such a high frequency was not found for the other 3 codon mutations. In a clinical follow-up study, Thr215 mutation appeared in the late stage of AZT treatment parallel with the emergence of AZT insusceptibility. It is worth noting that this Thr215 mutation to Tyr or Phe is a 2-nucleotide mutation in contrast to the 1-nucleotide mutations seen in the other 3 codons. Isolates with the single amino acid change of Thr215 of the RT-coding region obtained after long-term AZT treatment grew in the presence of 1 microM AZT. This single amino acid mutation in the Thr215 codon is the most important factor in AZT resistance.
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PMID:Predominance of codon 215 mutation in reverse transcriptase-coding region of 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 isolates after long-term AZT therapy. 870 9

Human immunodeficiency virus type 1 (HIV-1) isolates obtained prior to and during a combination therapy trial comparing zidovudine (AZT; 3'-azidothymidine) monotherapy with AZT plus 2',3'-dideoxyinosine (ddI) or AZT plus 2',3'-dideoxycytidine (ddC) were assessed for the development of drug resistance. Drug susceptibility was measured by using two different phenotypic assays, one that requires infection of peripheral blood mononuclear cells with HIV-1 isolated from cocultures and a second based on infection of HeLa CD4+ cells with recombinant virus containing the reverse transcriptase (RT) of the clinical isolate. In addition, genotypic assessment of resistance was obtained by DNA sequencing of the RT coding region. No difference in the development of AZT resistance was noted in isolates from individuals receiving AZT monotherapy or combination therapy. However, a low frequency of ddI or ddC resistance was seen in isolates from the combination arms, which may at least partially explain the enhanced efficacy observed with these drug combinations compared with monotherapy. It was noted from DNA sequencing that a relatively high frequency of the nonnucleoside RT inhibitor resistance mutation, codon 181 changed from encoding Tyr to encoding Cys, was present in some isolates both before and during nucleoside analog combination therapy. Since these patients were unlikely to have access to nonnucleoside RT inhibitors, it is probable that this mutation preexisted at a reasonable level in the wild-type virus population. Comparisons of the AZT susceptibility assays indicated a good correlation between the phenotypic and genotypic determinations. However, direct numerical comparisons between the phenotypic assays were not reliable, suggesting that valid comparisons of different resistance data sets will require the use of the same assay procedure.
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PMID:Human immunodeficiency virus type 1 drug susceptibility during zidovudine (AZT) monotherapy compared with AZT plus 2',3'-dideoxyinosine or AZT plus 2',3'-dideoxycytidine combination therapy. The protocol 34,225-02 Collaborative Group. 870 13

A large variety of carboxanilide and thiocarboxanilide derivatives in which the original oxathiin or aliphatic moieties present in the prototype compounds UC84 and UC38 were replaced by an (un) substituted furanyl, thienyl, phenyl, or pyrrole entity have been evaluated for activity against wild-type human immunodeficiency virus type 1 strain IIIB [HIV-1 (IIIB)] and a series of mutant virus strains derived thereof. The mutant viruses contained either the Leu-100-->Ile, Lys-103-->Asn, Val-106-->Ala, Glu-138-->Lys, Tyr-181-->Cys, or Tyr-188-->Leu mutation in their reverse transcriptase. Several 3-(2-methylfuranyl)- and 3-(2-methylthienyl)-thiocarboxanilide ester, (thio)ether, and oxime ether derivatives showed exquisitely potent antiviral activity against wild-type HIV-1 (50% effective concentration, 0.009 to 0.021 microM). The pentenylethers of the 2-methylfuranyl and 2-methylthienyl derivatives (i.e., 313, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]- 2-methyl-3-furancarbothioamide or UC-781, and 314, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl] -2-methyl-3-thiophenecarbothioamide or UC-82) proved virtually equally inhibitory for wild-type and the Ile-100, Ala-106, and Lys-138 mutant virus strains (50% effective concentration, 0.015 to 0.021 microM). Their inhibitory effect against the Asn-103 and Cys-181 reverse transcriptase mutant virus strains was decreased only four- to sevenfold compared with wildtype virus. UC-781 and UC-82 should be considered potential candidate drugs for the treatment of HIV-1-infected individuals.
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PMID:Identification of novel thiocarboxanilide derivatives that suppress a variety of drug-resistant mutant human immunodeficiency virus type 1 strains at a potency similar to that for wild-type virus. 872 19

We monitored a subject newly infected with a zidovudine-resistant human immunodeficiency virus type 1 strain and found that in the absence of drug, the viral population with the resistance-conferring tyrosine (TAC) codon 215 of reverse transcriptase was gradually replaced. By using standard formulas to model the effects of selection at a single locus in an asexual haploid population, the relative fitness gain of the viral population with a single mutation at codon 215 creating a serine (TCC) was calculated. We concluded that a viral population with a serine at reverse transcriptase codon 215 conferring zidovudine sensitivity was between 0.4 and 2.3% more fit.
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PMID:Human immunodeficiency virus fitness in vivo: calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase. 876 84

The high error rates characteristic of human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) are a presumptive source of the viral hypermutability that impedes prevention and therapy of acquired immunodeficiency syndrome (AIDS). We have analyzed two mutants of HIV-1 RT by conducting a comparative study of the accuracy of DNA synthesis. Each mutant bears a single amino acid substitution adjacent to the two aspartic acid residues at positions 185 and 186 in the highly conserved DNA polymerase active site. The first mutant, Met 184-->Leu (M184L), displays a marked reduction in both misinsertion and mispair extension, suggesting a fidelity of DNA synthesis significantly higher than that of the wild-type HIV-1 RT. The second mutant, Tyr 183-->Phe (Y183F), shows a decrease in mispair extension with no significant change in misincorporation. Thus, the overall pattern of error-proneness of DNA synthesis is: wild-type HIV-1 RT > Y183F > M184L. Taken together, it is possible that residues 183 and 184 contribute to the low fidelity of DNA synthesis characteristic of the reverse transcriptases of HIV-1, HIV-2 and possibly, of other lentiviruses. Our observations may bear on the nature of potential mutations responsible for resistance to the nucleoside analogs used in chemotherapy of AIDS.
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PMID:Mutational studies of human immunodeficiency virus type 1 reverse transcriptase: the involvement of residues 183 and 184 in the fidelity of DNA synthesis. 876 85


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