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)

A novel class of non-nucleoside triphosphate analogues, bearing hydrophobic groups sterically similar to nucleosides linked to the alpha-phosphate but lacking the chemical functional groups of nucleic acids, were tested against six different DNA polymerases (polymerases). Human polymerases alpha, beta and lambda, and Saccharomyces cerevisiae polymerase IV, were inhibited with different potencies by these analogues. On the contrary, Escherichia coli polymerase I and HIV-1 reverse transcriptase were not. Polymerase beta incorporated these derivatives in a strictly Mn++-dependent manner. On the other hand, polymerase lambda could incorporate some alkyltriphosphate derivatives with both Mg++ and Mn++, but only opposite to an abasic site on the template strand. The active site mutant polymerase lambda Y505A showed an increased ability to incorporate the analogues. These results show for the first time that neither the base nor the sugar moieties of nucleotides are required for incorporation by family X DNA polymerases.
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PMID:Incorporation of non-nucleoside triphosphate analogues opposite to an abasic site by human DNA polymerases beta and lambda. 1604 33

The extent to which human telomerase reverse transcriptase (hTERT) mRNA and its splice variants control telomerase activity in human cancers is controversial. Telomerase and hTERT mRNA were assessed quantitatively in paired samples of gastric adenocarcinoma and adjacent normal tissue. Splice variants within the hTERT reverse transcriptase domain (alpha, beta, alphabeta) were detected by RT-PCR. In gastric adenocarcinoma, compared to normal tissue, median telomerase activity increased significantly (from 0 total product generated [tpg; 95% confidence interval CI, 0-2.3] to 16.1 tpg [95% CI, 3.7-97]; P = 0.008) and median hTERT mRNA levels also increased (from 2.21 [95% CI, 1.40-4.62] to 7.08 [95% CI, 3.26-10.8]; P = 0.0054). hTERT mRNA and telomerase activity correlated in normal gastric mucosa (r = 0.819, P = 0.0002). Alpha, beta, and alphabeta deletions were similar in both groups. We conclude that hTERT mRNA partially regulates telomerase activity in normal gastric mucosa and gastric adenocarcinoma. In contrast, hTERT mRNA splicing is not involved in the regulation of enzyme activity.
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PMID:HTERT mRNA partially regulates telomerase activity in gastric adenocarcinoma and adjacent normal gastric mucosa. 1604 76

There is a growing body of evidences suggesting the important role of vitamin A for the optimal maintenance and functioning of immune system. It is now well established that retinoic acid (RA), a product of oxidative metabolism of vitamin A, is the most active vitamin A derivative physiologically. In this study, we examined the role of RA in B cell maturation in T cell-dependent activation pathway. RA enhanced the immunoglobulin synthesis by tonsillar B cells in anti-CD40 plus IL-10-mediated culture system. When the kinetics of B cells with different phenotypic characteristics were monitored during 9 days culture period by flow cytometric analysis, it displayed the increase of the B cells with plasma cell phenotype (CD38+/CD20-/IgD-) in the presence of RA. As resting B cells from tonsil expressed mRNA of the RA receptors alpha, beta, gamma and RXRalpha by reverse transcriptase-polymerase chain reaction, it is certain that RA effect is mediated by RA receptors. Taken together, this study showed that retinoic acid could accelerate the differentiation of B cells maturing into antibody producing cells.
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PMID:All-trans-retinoic acid accelerates the differentiation of human B lymphocytes maturing into plasma cells. 1627 19

Atp2b2 encodes the plasma membrane Ca(2+)-ATPase type 2 (PMCA2) expressed in various tissues, including stereocilia of cochlear and vestibular hair cells, cerebellar Purkinje cells, and lactating mammary epithelia. Mutations of the gene lead to deafness, ataxia, and reduced Ca(2+) levels in milk. Heterozygous mutants also have abnormal hearing, suggesting that precise regulation of Atp2b2 is required for normal function. In this study, we describe Atp2b2 5'-untranslated region genomic structure and transcript usage in mice. Using 5'-rapid amplification of cDNA ends, we observed four transcripts: types alpha, beta, mu and delta, each splicing into a common ATG-containing exon. Types alpha and beta correspond to previously published mammalian cDNA sequences. Types mu and delta constitute novel 5'-untranslated region sequences, and were observed at high levels only in lactating mammary gland. Using real-time reverse transcriptase polymerase chain reaction, we quantified relative transcript usage across several tissues. We show that alpha and beta are abundant throughout the CNS, as well as the cochlea. When we microdissected the cochlea into hair cell and spiral ganglion containing fractions, we found that cochlear hair cell expression is mediated through the type alpha transcript. In situ hybridization studies in cerebellum using exon-specific probes revealed that alpha dominates in Purkinje neurons, while beta is enriched in cerebellar granule neurons. We compared 5'-untranslated region sequence across multiple species, and found high conservation around the first exons for alpha and beta in mammals, but not other species. The regions around the mu and delta first exons are highly conserved between rat and mouse, but less so with other species. Our results show that expression of Atp2b2 is highly regulated, using four different transcriptional start regions, two of which are differentially expressed in neuronal tissue. This suggests that unique regulatory mechanisms are used to control Atp2b2 expression in different types of cells.
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PMID:Atp2b2, encoding plasma membrane Ca2+-ATPase type 2, (PMCA2) exhibits tissue-specific first exon usage in hair cells, neurons, and mammary glands of mice. 1667 32

The transmembrane metalloproteases angiotensin-converting enzyme (ACE) and tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE/ADAM-17) have been associated with inflammation, cancer progression and angiogenesis. Few investigations into the regulation of these enzymes by physiological stimuli have been reported. In this study, we investigated the influence of interferons (IFNs) type I (alpha, beta) and II (gamma) on ACE and TACE expression of human leukemic NB4 cells and monocytes. We assessed the expression of proteases by reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence analyses. IFNgamma, but not type I IFNs, upregulated membrane ACE in a dose- and time-dependency and this was reflected by the increase of ACE enzymatic activity and ACE mRNA. ACE upregulation was dependent on protein synthesis. Treatment of the interferon responsive factor 1 (IRF1)-unresponsive HepG2 cell line with IFNgamma did not affect ACE expression, thus suggesting the participation of the IRF1 signaling pathway in IFNgamma-mediated ACE upregulation in myeloid cells. In contrast, both types of IFNs, in a dose- and time-dependent manner, downregulated surface TACE without affecting TACE transcript. Soluble TACE was not detected in the medium of IFN-treated cells. IFNgamma-mediated decrease of surface TACE in NB4 cells was reversible, and correlated with an increase in intracellular TACE, suggesting that cell surface TACE was internalized in response to IFNs. These findings, showing the presence of IFN-dependent controlled mechanisms by which ACE and TACE levels are regulated in human normal and leukemic myeloid cells, may have implications in the context of current investigations on the therapeutic potential of IFNs.
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PMID:Differential regulation of tumor necrosis factor-alpha-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells. 1679 29

We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
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PMID:Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine. 1754 98

A novel class of putative progestin binding proteins has been recently identified as potential mediators of rapid nongenomic hormone actions. The proteins designated membrane progestin receptor (mPR) alpha, beta, and gamma were initially discovered in fish and shown to have a role in oocyte maturation. The predicted multiple membrane spanning domain structure of the mPRs resembles that of heptahelical G-protein-coupled receptors. Phylogenetic analysis indicated that the mPRs belong to the large progestin and adiponectin Q receptor (PAQR) gene family. Based on the reported expression of the 3 mPRs in hormone-responsive tissues of the female reproductive tract and on the role of steroid hormones in cancer, we investigated the expression of these novel progestin receptors in epithelial tumors of the ovary. The transcript levels of the 3 human mPR/PAQRs were assessed by semiquantitative reverse transcriptase polymerase chain reaction in 28 ovarian samples, including normal tissues, cystadenomas, borderline tumors, and common types of ovarian carcinomas. Two of the 3 transcripts for the mPR/PAQRs proteins appeared differentially expressed in the tumors examined. Expression of mPR alpha and beta was demonstrated in ovarian tumors at both messenger RNA and protein level, and their expression appeared to be independent of the expression of the classic nuclear progestin receptors. Expression of mPR gamma (PAQR V) was elevated in endometrioid and clear cell carcinomas, 2 related neoplastic counterparts of hormonally responsive tissues, suggesting a potential role of the mPR/PAQRs in the pathogenesis of epithelial ovarian tumors.
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PMID:Expression profile of heptahelical putative membrane progesterone receptors in epithelial ovarian tumors. 1847 32

Mucolipidosis II (ML II) and mucolipidosis III (ML III) are diseases in which the activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent or reduced, respectively. In the absence of mannose phosphorylation, trafficking of lysosomal hydrolases to the lysosome is impaired. In these diseases, mistargeted lysosomal hydrolases are secreted into the blood, resulting in lysosomal deficiency of many hydrolases and a storage-disease phenotype. GlcNAc-phosphotransferase is a multimeric transmembrane enzyme composed of three subunits (alpha, beta and gamma) encoded by two genes -GNPTAB and GNPTG. Defects in GNPTAB result in ML II and III whereas mutations in GNPTG were only found in ML III patients. We have performed a molecular analysis of the GNPTAB and GNPTG genes in 13 mucolipidosis II and III patients (10 Portuguese, one Finnish, one Spanish of Arab origin and one Indian). Mutations were identified by the study of both cDNA and gDNA. The GNPTAB and GNPTG mRNA expressions were determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The study led to the identification of 11 different mutations. Eight of these mutations are novel, six in the GNPTAB gene [c.121delG (V41FfsX42), c.440delC (A147AfsX5), c.2249_50insA (N750KfsX8), c.242G>T (W81L), c.1208T>C (I403T) and c.1999G>T (p.E667X)] and two in the GNPTG gene [c.610-1G>T and c.639delT (F213LfsX7)]. With regard to the mRNA expression studies, the values obtained by qRT-PCR indicate the possible existence of feedback regulation mechanisms between alpha/beta and the gamma subunits.
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PMID:Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations. 1965 62

Celiac disease (CD) is a chronic enteropathy triggered by intake of gliadin, the toxic component of gluten. This study aims at evaluating the capacity of different Bifidobacterium strains to counteract the inflammatory effects of gliadin-derived peptides in intestinal epithelial (Caco-2) cells. A commercial extract of several gliadin (Gld) types (alpha, beta, gamma, [symbol: see text] ) was subjected to in vitro gastrointestinal digestion (pepsin at pH 3, pancreatin-bile at pH 6), inoculated or not with cell suspensions (10(8) colony forming units/ml) of either B. animalis IATA-A2, B. longum IATA-ES1, or B. bifidum IATA-ES2, in a bicameral system. The generated gliadin-derived peptides were identified by reverse phase-HPLC-ESI-MS/MS. Caco-2 cell cultures were exposed to the different gliadin peptide digestions (0.25 mg protein/ml), and the mRNA expression of nuclear factor kappa-B (NF-kappaB), tumor necrosis factor alpha (TNF-alpha), and chemokine CXCR3 receptor were analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in stimulated cells. The production of the pro-inflammatory markers NF-kappaB p50, TNF-alpha, and IL-1beta (interleukine 1beta) by Caco-2 cells was also determined by ELISA. The peptides from gliadin digestions inoculated with bifidobacteria did not exhibit the toxic amino acid sequences identified in those noninoculated (alpha/beta-Gld [158-164] and alpha/beta-Gld [122-141]). The RT-PCR analysis evidenced a down-regulation in mRNA expression of pro-inflammatory biomarkers. Consistent with these results the production of NF-kappaB, TNF-alpha, and IL-1beta was reduced (18.2-22.4%, 28.0-64.8%, and abolished, respectively) in cell cultures exposed to gliadin digestions inoculated with bifidobacteria. Therefore, bifidobacteria change the gliadin-derived peptide pattern and, thereby, attenuate their pro-inflammatory effects on Caco-2 cells.
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PMID:Bifidobacteria inhibit the inflammatory response induced by gliadins in intestinal epithelial cells via modifications of toxic peptide generation during digestion. 2005 69

Human telomerase reverse transcriptase (hTERT) expression level may not always correlate with telomerase activity. Although the positions of the spliced sites suggest that many of the variants do not code for functional reverse transcriptase, the functions of the spliced variants of hTERT are unknown. We analyzed hTERT splicing patterns with respect to telomerase activity in breast cancer. We examined telomerase activity by telomeric repeat amplification protocol (TRAP) assay and detected spliced variants of hTERT by reverse transcription-polymerase chain reaction (RT-PCR). Of 45 breast cancer patients, 38 (84%) were found to express telomerase activity and 41 (91%) expressed hTERT. In patients with telomerase activity, 14 (37%) expressed all four types of variants (full length, alpha, beta, and alpha/beta). Eleven patients (29%) expressed both the full-length and beta variant. Eight patients (22%) expressed the beta variant only and 3 (8%) expressed the full-length type only. When comparing telomerase activity to the expression of splicing variants, a tendency was found for lower telomerase activity in patients expressing the beta variant only (45 +/- 11) versus those expressing all four types (64 +/- 32) and those coexpressing the full-length type with the beta variant (61 +/- 22) (p = 0.06, respectively). In patients with both full-length and beta variants coexpression, increment of beta variant showed a decreased telomerase activity regardless of the full-length variant expression (p = 0.027). Telomerase activity changed with alternative splicing of the full-length and beta variants expression of hTERT in breast cancer.
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PMID:Changes of telomerase activity by alternative splicing of full-length and beta variants of hTERT in breast cancer patients. 2022 59


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