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)

Retinoic acids, vitamin A-related compounds, are known to be inhibitors of telomerase. We found that fucoxanthin from the sea alga Petalonia bingamiae is a potent inhibitor of mammalian replicative DNA polymerases (i.e., pol alpha, delta and epsilon). Since fucoxanthin is a carotenoid (provitamin A-related) compound, we characterized the biochemical modes of vitamin A-related compounds including vitamin A and provitamin A in this report. Subsequently, we found that fucoxanthin, all-trans retinal (RAL, vitamin A aldehyde) and all-trans retinoic acid (RA, vitamin A acid) inhibited the activities of replicative DNA polymerases with IC(50) values of 18-190, 14-17 and 8-30 microM, respectively. On the other hand, all-trans retinol (vitamin A) did not influence any of the DNA polymerase activities. RA inhibited not only the activities of pol alpha, delta and epsilon with IC(50) values of 30, 28 and 8 microM, respectively, but of pol beta with an IC(50) value of 27 microM. The tested vitamin A-related compounds did not influence the activities of DNA polymerases from a higher plant, cauliflower, prokaryotic DNA polymerases, or DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. RAL and RA should be called selective inhibitors of mammalian DNA polymerases including telomerase, and RAL was a specific inhibitor of mammalian replicative DNA polymerases. As expected from these results in vitro, some of them could prevent the growth of NUGC-3 human gastric cancer cells, and especially RAL was a potent antineoplastic agent with an LD(50) value of 19 microM. The cells were halted at G1 phase in the cell cycle by RAL.
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PMID:Vitamin A-related compounds, all-trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases. 1195 16

Nogo is a novel myelin-associated inhibitor of neurite outgrowth which regulates stable neuronal connections during axonal regeneration following injury in the adult mammalian central nervous system (CNS). Because cytokines and neurotrophic factors play a key role in inflammation-related axonal regeneration, we investigated: (i) the constitutive expression of Nogo and the Nogo receptor (NgR) mRNA in human neural cell lines; (ii) Nogo and NgR mRNA levels in the NTera2 human teratocarcinoma cell line during retinoic acid (RA)-induced neuronal differentiation; and (iii) their regulation in NTera2-derived differentiated neurones (NTera2-N) after exposure to a battery of cytokines and growth factors potentially produced by activated glial cells at post-traumatic inflammatory lesions in the CNS. By reverse transcriptase-polymerase chain reaction analysis, the constitutive expression of Nogo-A, the longest isoform of three distinct Nogo transcripts and NgR mRNA was identified in a wide variety of human neural and non-neural cell lines. By Northern blot analysis, the levels of Nogo-A mRNA were elevated markedly in NTera2 cells following RA-induced neuronal differentiation, accompanied by an increased expression of the neurite growth-associated protein GAP-43 mRNA. In contrast, Nogo-A, Nogo-B, NgR and GAP-43 mRNA levels were unaltered in NTera2-N cells by exposure to basic fibroblast growth factor, brain-derived neurotrophic factor, glia-derived neurotrophic factor, tumour necrosis factor-alpha, interleukin-1beta, dibutyryl cyclic AMP or phorbol 12-myristate 13-acetate. These results indicate that both Nogo-A and NgR mRNA are coexpressed in various human cell types, including differentiated neurones, where their expression is unaffected by exposure to a panel of cytokines and neurotrophic factors which might be involved in inflammation-related axonal regeneration in the CNS.
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PMID:Cytokines and neurotrophic factors fail to affect Nogo-A mRNA expression in differentiated human neurones: implications for inflammation-related axonal regeneration in the central nervous system. 1197 96

Human telomerase, a cellular reverse transcriptase specifically activated in most malignant tumors and usually inactive in normal somatic cells, plays an important role in immortalization and tumorigenesis. Early reports have indicated that terminal differentiation of various cells is associated with a rapid inhibition of telomerase activity, preceded by a down-regulation of telomerase reverse transcriptase (hTERT) mRNA. Recently, we have shown that telomerase can be repressed by all-trans retinoic acid (ATRA) independently of terminal maturation during long-term ATRA treatment of the maturation-resistant promyelocytic leukemia cell line (NB4-R1), leading to shortening of telomeres and cell death, events overcome by ectopic hTERT expression. Here, we report the isolation of a variant of NB4-R1 cells (NB4-R1(SFD)), which bypasses this death step, because of a re-activated telomerase, despite the continuous presence of ATRA. While unresponsive to a long-term maturation independent regulation of telomerase by ATRA, these cells retain a functional pathway of telomerase down-regulation associated with retinoid-induced maturation. These findings reinforce the notion that two distinct pathways of telomerase regulation by retinoids co-exist in APL cells. Noteworthy, we show that the slow developing mechanism, that causes death of maturation-resistant cells, is subjected to a new type of retinoid-resistance as yet not understood.
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PMID:A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation. 1198 43

c-Myc regulates cellular proliferation, differentiation, and apoptosis. Temporal expression of c-Myc during all-trans-retinoic acid (RA)-mediated neural differentiation in murine embryonic stem cell (ES) was investigated. Correlation to the modulation of dimerizing partners Max and Mad that may influence c-Myc signaling and transcription regulation was elucidated for the first time in these cells. In RA-treated cells, increase in c-myc mRNA was detected by reverse transcriptase polymerase chain reaction on days 11 and 14 of differentiation compared with the vehicle-treated controls. The results were further corroborated by ribonuclease protection assay (RPA). Western blots revealed an increase in c-Myc protein only on day 14 of differentiation in RA-treated cells. Increases in max and mad gene transcription detected by RPA at times of elevated c-Myc in RA-treated ES cells suggest that a transient increase in c-Myc protein expression may influence differential dimerization of Myc partners needed for signaling in the neural differentiation of ES cells.
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PMID:Modulation of c-myc, max, and mad gene expression during neural differentiation of embryonic stem cells by all-trans-retinoic acid. 1206 75

Retinoic acid (RA) derived from vitamin A is necessary for, among other things, mammalian embryonic development. Although the impact of RA-dependent gene-regulation on embryonic development has been examined through genetic disruption of the retinoid receptors, the understanding of the underlying molecular mechanism remain unclear, in part, due to the difficulty in identifying RA-regulated genes in an intact embryo. We report here that RA-regulated genes can be identified from total RA-deficient embryos created by retinol-binding protein antisense (RBP-AS) oligodeoxynucleotide treatment in conjunction with differential display. Of the 28 genes isolated, 15 genes matched known genes in the GenBank database and the others either represented EST sequences or encoded novel genes. Semi-quantitative reverse transcriptase-polymerase chain reaction verified that the mRNA levels of mouse DN 38, COL VI 3 alpha, cul-1, alpha-tropomyosin, and PP2A-C alpha were substantially increased, whereas mouse Msh 2, Ndufa2, Ribosomal protein S19, sFRP-1, GDAP-10 and mSmcD were significantly decreased in vitamin A deficient (VAD) embryos compared to the control embryos. The utility of the method is exemplified by our finding that several genes in the Wnt signaling pathway are vitamin A regulated in day 9.0 post coitum (p.c.) embryos.
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PMID:Identification of known and novel genes whose expression is regulated by endogenous retinoic acid during early embryonic development of the mouse. 1217 13

Retinyl ester, the most abundant form of vitamin A (retinol), is synthesized by the enzyme lecithin:retinol acyltransferase (LRAT). Previously, we cloned a 2.5 kb LRAT cDNA from rodent liver which codes for functional LRAT activity. However, Northern blots of tissues probed with the 2.5 kb cDNA revealed the presence of a larger transcript of approximately 5 kb as well as several smaller transcripts. To elucidate the nature of the large LRAT transcript, a high-molecular-mass adrenal gland cDNA library was screened. Two similar clones of 3962 and 3187 nt were identified which appeared to be part of the 3'-untranslated region (UTR) of a 5358 nt LRAT mRNA. The 5.3 kb cDNA was then amplified from liver by reverse transcriptase PCR (RT-PCR) and demonstrated to encode functional LRAT activity. The 3'-UTR of the 5.3 kb cDNA contains several AAUAAA polyadenylation signals. Analysis of the 3' ends of LRAT mRNA transcripts from liver, intestine and testis showed the usage of both canonical and non-canonical polyadenylation signals. To further analyse the LRAT mRNAs expressed in vivo, Northern blot analysis was performed using four probes spanning sections from the 5' end to the distal 3' end of the 5.3 kb LRAT cDNA. The results show that the major 5.3 kb transcript uses the canonical signal AAUAAA located at nt 5308, and the major short transcript of approximately 1.5 kb uses the non-canonical signal AUUAAA located at nt 1330. The 5.3 kb LRAT transcript was predominant in the liver of retinoic acid-repleted vitamin A-deficient rats, coincident with increased quantitative expression of LRAT mRNA and enzyme activity. The differential usage of these polyadenylation signals can explain the presence of multiple LRAT mRNA transcripts which are expressed in different tissue-specific patterns.
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PMID:Cloning and molecular expression analysis of large and small lecithin:retinol acyltransferase mRNAs in the liver and other tissues of adult rats. 1220 19

Melanoma-inhibiting activity/cartilage-derived retinoic acid-sensitive protein, a 11 kDa protein, is mainly expressed in cartilage during embryogenesis, and is related to invasion, metastasis, and immunomodulation of melanoma and glioma cells in vivo and in vitro. Here, we describe an alternative splice product of this gene termed melanoma-inhibiting activity (splice), lacking exon 2 of the original protein. A predicted frameshift by alternate splicing results in a unique C-terminal portion of the protein. Consistent with this, a protein migrating at the predicted molecular weight of the splice form (3.5 kDa) was detected using an N-terminal specific antibody. This band was undetectable when using a C-terminal specific antibody. In addition, we describe the expression pattern of melanoma-inhibiting activity (splice) in different human tumors. Expression was shown in tissue samples of five of six primary melanomas, 11 of 12 primary sites of metastatic melanomas, 10 of 10 systemic metastases of melanomas, four of four central nervous system metastases of melanomas, six of eight primary melanoma cultures, and five of five melanoma cell lines. Only a faint signal was obtained in tissue samples of five of six naevi. Interestingly, seven of eight nonmelanocytic tissue samples and five of seven glioma cell lines showed weak expression of melanoma-inhibiting activity (splice). Approaching first functional aspects, reverse transcriptase-polymerase chain reaction showed weak expression of melanoma-inhibiting activity (splice) in relation to melanoma-inhibiting activity in nonmelanocytic and strong expression in melanocytic cells. Staining with a specific anti-serum raised against a synthetic peptide resembling the amino acid sequence of melanoma-inhibiting activity (splice) showed a more nuclear staining pattern in comparison with melanoma-inhibiting activity. Furthermore, incubation of melanoma and glioma cell cultures with transforming growth factor-beta2 showed inverse regulation of the mRNA of melanoma-inhibiting activity and melanoma-inhibiting activity (splice), both suggesting also a different function within the physiologic role of this unique family of proteins. Melanoma-inhibiting activity (splice) has no homology to any other known protein so far. Whereas the biologic function of melanoma-inhibiting activity (splice) is not clear yet, it might provide a relevant diagnostic and therapeutic tool for malignant melanomas.
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PMID:Cloning and characterization of the expression pattern of a novel splice product MIA (splice) of malignant melanoma-derived growth-inhibiting activity (MIA/CD-RAP) [corrected]. 1223 Apr 96

Individuals with acute promyelocytic leukemia (APL) usually express 1 of 3 primary hybrid transcripts associated with a t(15;17). The 3 fusion transcripts are the result of heterogeneous breakpoint cluster regions (bcr) within the promyelocytic leukemia (PML) gene and are denoted bcr1 (long), bcr2 (variant), and bcr3 (short) forms. Many researchers have shown that real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of the involved transcript is a valuable tool for monitoring APL and its treatment. In addition, some research suggests that identification of a specific breakpoint region may be used to predict an individual's likelihood of relapse and possibly their response to all-trans retinoic acid treatment. We describe the first reported 1-step multiplex RT-PCR assay capable of t(15;17) fusion transcript real-time relative quantitation and simultaneous transcript form identification in 2 reactions. This assay uses a novel dual-probe technique to achieve what has required a laborious procedure of 2 or more reactions followed by postamplification analysis. We found a correlation of 100% in detection and breakpoint determination of the long, short, and variant forms with a breakpoint 5' to nucleotide 1709 compared with results from traditional methods.
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PMID:A novel method for the detection, quantitation, and breakpoint cluster region determination of t(15;17) fusion transcripts using a one-step real-time multiplex RT-PCR. 1252 Jul 9

Neurogenin3 is a member of the basic helix-loop-helix ('bHLH') family of transcription factors. It plays a crucial role in the commitment of embryonic endoderm into the pancreatic differentiation programme. This factor is considered to act upstream of a cascade of other transcription factors, leading to the fully differentiated endocrine phenotype. Direct observation of the sequential activation of these factors starting from Neurogenin3 had never been demonstrated. By using retinoic acid-derived-endoderm F9 cells as a model, the present study indicates that the ectopic expression of Neurogenin3 is able to start the differentiation pathway of endocrine pancreas. Neurogenin3 triggers the expression of several pancreatic transcription factors following a well defined temporal activation sequence. By reverse transcriptase PCR, immunohistochemistry and RIA, it is shown that stable transfected cells are able to form embryod bodies that produce insulin in response to glucose stimulation. This is the first report of a differentiation event induced by the ectopic expression of a transcription factor in embryonic pluripotent stem cells.
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PMID:Neurogenin3 triggers beta-cell differentiation of retinoic acid-derived endoderm cells. 1252 76

A sensitive quantitative-competitive reverse transcriptase-polymerase chain reaction method was developed to measure micro-opioid receptor (MOR) mRNA expression in SHSY-5Y neuroblastoma cells. Differentiation of SHSY-5Y cells with either retinoic acid (RA) or 12-o-tetradecanoyl-phorbol-13-acetate (TPA) significantly increased MOR mRNA levels. Morphine treatment (10 microM) for 24 h decreased MOR mRNA levels in control, as well as RA- and TPA-differentiated cells. In contrast, chronic exposure to the opioid peptides endomorphin-1 or endomorphin-2 significantly increased MOR mRNA levels in undifferentiated and RA-differentiated cells. An opioid antagonist, naloxone, reversed the morphine and endomorphin-1 and -2 effects on MOR mRNA levels in undifferentiated SHSY-5Y cells, but naloxone had differential reversing effects on the agonists' regulation of MOR mRNA in RA- or TPA-differentiated cells. To investigate whether the changes in MOR mRNA expression paralleled changes in MOR receptor function, intracellular cAMP accumulation in SHSY-5Y cells was measured. After chronic treatment with morphine, forskolin-induced cAMP levels in SHSY-5Y cells were significantly higher than those of untreated control cells. In contrast, forskolin-induced cAMP accumulation levels were lower in cells treated with endomorphin-1 or -2 than in untreated control cells. Together, our studies indicate that the opioid alkaloid morphine and the opioid peptides endomorphin-1 and -2 differentially regulate MOR mRNA expression and MOR function in SHSY-5Y cells.
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PMID:Morphine and endomorphins differentially regulate micro-opioid receptor mRNA in SHSY-5Y human neuroblastoma cells. 1275 18


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