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)

E1000, the most drug-resistant subline from the E-series (CCRF-CEM/E16 to E1000), has been previously shown to express high mRNA levels from two ABC transporter genes associated with multidrug resistance, ARA and MRP. The expression and amplification of both genes has now been characterized for each member of the E-series of drug-resistant sublines and is reported here. Both ARA [detected by reverse transcriptase polymerase chain reaction (RT-PCR)] and MRP (detected by Northern blot analysis) were expressed at low levels in the sensitive parental CEM cell line. An equivalent level of MRP mRNA expression was detected throughout the CEM, E16, E25 and E50 sublines, and there was increasing expression in the E100, E200 and E1000 sublines. ARA expression was not detected in the E16, E25, E50 and E100 sublines but was detected by both RT-PCR and Northern blot analysis in the E200 and E1000 sublines. Southern blot analysis indicated the increased levels of MRP and ARA expression resulted from gene amplification and that MRP was first amplified in the E100 subline and ARA in the E200 subline, suggesting that the two genes were not initially co-amplified. Cytogenetic analysis of E1000 cells demonstrated a large addition to chromosome 16p, around the region where the ARA and MRP genes are located. Increased expression of ARA is associated with increased colchicine resistance in the E-series of sublines and combined with MRP may account for their resistance phenotype.
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PMID:Amplification and expression of the ABC transporters ARA and MRP in a series of multidrug-resistant leukaemia cell sublines. 964 17

The rat monoclonal antibody LMR-12 was shown earlier to react with a plasma membrane protein, upregulated in multidrug-resistant cell lines. In this study, we observed distinct LMR-12 staining in 36 out of 55 non-drug-selected tumour cell lines, including melanomas, renal cell-, colon- and lung carcinomas, whereas in other tumour types, such as leukaemia and ovarian cancer, LMR-12 staining was generally low or absent. The cDNA encoding the LMR-12 antigen was isolated from a library of the multidrug-resistant human fibrosarcoma cell line HT1080/DR4 by expression cloning in MOP8 cells. Sequence analysis showed that the LMR-12 antigen is identical to the major histocompatibility complex class I molecule beta 2-microglobulin (beta2-m). The LMR-12/ beta2-m staining results were confirmed by mRNA microarray data from an independent National Cancer Institute study, as well as by newly obtained reverse transcriptase polymerase chain reaction data. Further analysis of the microarray data showed that beta2-m levels closely reflected levels of major histocompatibility complex class I heavy chains and the transporter associated with antigen processing. Since the ABC transporter associated with antigen processing was previously shown to contribute to multidrug-resistance, it may very well be that the observed LMR-12/ beta2-m levels are secondary to (elevated) levels of the transporter associated with antigen processing. A perspective arising from the present study is that drug resistant tumour cells may, by having elevated levels of major histocompatibility complex related molecules, be particular good candidates for alternative therapeutic therapies, such as cytotoxic T cell mediated immune-therapies.
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PMID:Increased expression of beta 2-microglobulin in multidrug-resistant tumour cells. 1208 91

Borrelia burgdorferi undergoes differential gene expression during transmission from its tick vector to a vertebrate host. The addition of blood to a spirochete culture at 35 degrees C for 48 h had a dramatic effect on gene expression of this organism. Utilizing B. burgdorferi whole genome DNA arrays, we compared the transcriptomes of the spirochetes following a 2-day temperature shift with blood and without blood. Using combined data from three independent RNA isolations we demonstrated that the addition of blood led to a differential expression of 154 genes. Of these, 75 genes were upregulated, with 49 (65%) of them encoded on plasmids. Blood supplementation of cultures also resulted in the downregulation of 79 genes, where 56 (70%) were plasmid encoded. We verified our results by reverse transcriptase PCR of several genes in both flat and feeding ticks. In the 2-day experiment we observed the effect that exposure to increased temperature and blood combined had on B. burgdorferi gene expression at this crucial time when the spirochetes begin to move from the vector to a new vertebrate host. These changes, among others, coincide with the upregulation of the chemotaxis and sensing regulons, of the lp38-encoded ABC transporter, of proteases capable of remodeling the outer surface of the spirochetes, and of the recombination genes of cp32 as a transient or initial part of the stress response of the phage. These are all functions that could cause or facilitate the changes that spirochetes undergo following a blood meal in the tick.
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PMID:Combined effects of blood and temperature shift on Borrelia burgdorferi gene expression as determined by whole genome DNA array. 1532 40

GdhR is a meningococcal transcriptional regulator that was previously shown to positively control the expression of gdhA, encoding the NADP-specific L-glutamate dehydrogenase (NADP-GDH), in response to the growth phase and/or to the carbon source. In this study we used reverse transcriptase-PCR-differential display (to identify additional GdhR-regulated genes. The results indicated that GdhR, in addition to NADP-GDH, controls the expression of a number of genes involved in glucose catabolism by the Entner-Doudoroff pathway and in l-glutamate import by an unknown ABC transport system. The genes encoding the putative periplasmic substrate-binding protein (NMB1963) and the permease (NMB1965) of the ABC transporter were genetically inactivated. Uptake experiments demonstrated an impairment of L-glutamate import in the NMB1965-defective mutant in the absence or in the presence of a low sodium ion concentration. In contrast, at a sodium ion concentration above 60 mM, the uptake defect disappeared, possibly because the activity of a sodium-driven secondary transporter became predominant. Indeed, the NMB1965-defective mutant was unable to grow at a low sodium ion concentration (<20 mM) in a chemically defined medium containing L-glutamate and four other amino acids that supported meningococcal growth, but it grew when the sodium ion concentration was raised to higher values (>60 mM). The same growth phenotype was observed in the NMB1963-defective mutant. Cell invasion and intracellular persistence assays and expression data during cell invasion provided evidence that the l-glutamate ABC transporter, tentatively named GltT, was critical for meningococcal adaptation in the low-sodium intracellular environment.
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PMID:Identification of a meningococcal L-glutamate ABC transporter operon essential for growth in low-sodium environments. 1649 45

The O-antigen-encoding region in the genomes of 14 isolates of Coxiella burnetii was examined by PCR. Five phase I isolates (Nine Mile clone 7, KAV, Ohio, Henzerling RSA 343, Q173) were analyzed and no deletions were detected. Two other isolates of unknown phase (Scottish, WAV) were examined, but no deletions were detected. In contrast, RSA 514 and three phase II isolates (Nine Mile phase II clone 4, Nine Mile phase II clone 1, Nine Mile Baca) contained large deletions, and the latter two were further characterized by DNA sequencing. Three other phase II isolates (Henzerling RSA 331, M44, Australian QD) contained no apparent deletions. Reactivity to phase I- and phase II-specific antibodies by immunofluorescence assay was used to further characterize isolates. Selected ORFs in Australian QD and M44 DNA were sequenced to detect mutations, and no significant changes were found. Australian QD RNA was examined by reverse transcriptase-PCR specific to the four ORFs hypothesized to encode the O-antigen sugar virenose, which this isolate has been shown to lack, as well as one that is predicted to encode part of the O-antigen ABC transporter. Each of these five genes was found to be expressed.
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PMID:Analysis of the O-antigen biosynthesis regions of phase II isolates of Coxiella burnetii. 1715 23

trans-Resveratrol is a polyphenol present in several plant species. Its chemopreventive properties against several diseases have been largely documented. To validate a model for the study of the factors influencing its biological fate at the hepatic level, the metabolism and the efflux of resveratrol were studied in the human hepatoblastoma cell line, HepG2. Comparative high-performance liquid chromatography analysis of cell culture media before and after deconjugation showed that resveratrol was rapidly conjugated; at the concentration of 10 microM, it was entirely metabolized at 8 h of incubation. Two main resveratrol metabolites, monosulfate and disulfate, were identified by atmospheric pressure chemical ionization-mass spectrometry, thanks to their quasi-molecular ion and their characteristic fragmentation. To correlate with the auto-induction of resveratrol metabolism evidenced in HepG2 cells after a pretreatment for 48 h with 10 microM resveratrol, the inducibility of phase II enzymes by resveratrol was studied by real-time quantitative reverse transcriptase-polymerase chain reaction and flow cytometry. Observed, in particular, were an increase in mRNA expression levels of three metabolizing enzymes, two isoforms of UDP-glucuronosyltransferases, UGT1A1 and UGT2B7 (5-fold increased), and a sulfotransferase, ST1E1, in cells pretreated for 24 h with 10 microM resveratrol. These results were correlated with an increase in protein expression, especially after 48 h of treatment. On the other hand, the intracellular resveratrol retention in cells treated with MK571 (3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid), a multidrug resistance-associated protein inhibitor, strongly suggests the involvement of this ABC transporter family in the efflux of resveratrol conjugates from human liver.
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PMID:Resveratrol in human hepatoma HepG2 cells: metabolism and inducibility of detoxifying enzymes. 1728 90

Imatinib (Glivec, Gleevec, STI571) is a small tyrosine kinase inhibitor that is currently in phase II clinical trials in patients with recurrent glioblastoma. Its therapeutic benefit is minimal, although it is greater in some patients when combined with hydroxyurea. Imatinib is transported by human and rodent ATP-binding cassette (ABC) transporters like P-glycoprotein (Pgp) and the breast cancer resistance protein (BCRP). We have investigated whether ABC transporters determine the pharmacokinetics of imatinib and its pharmacological active metabolite CGP74588 in rat C6 glioma cells. ABC transporter expressions were measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). C6 cells express high concentrations of the Pgp-encoding gene Mdr1b and a 10-fold smaller amount of the Pgp-encoding gene Mdr1a. The relative expression of ABC transporter genes are: Mdr1b>Mrp4>Mrp1>Mrp5>Mdr1a>Mrp3>Mrp2>Bcrp. The accumulation of imatinib into C6 cells increased linearly with the extracellular concentration of imatinib (0.5-50microM) and was not increased by zosuquidar (selective Pgp inhibitor) or elacridar (inhibitor of both Pgp and Bcrp). In contrast, there was less CGP74588 than imatinib in C6 cells and its concentration increased with the extracellular concentration in a sigmoid fashion. Lastly, 10microM valspodar (selective Pgp inhibitor), elacridar and zosuquidar all increased the accumulation of CGP74588 by 2.5-fold. Thus CGP74588 is readily transported by the Pgp in rat C6 gliomas cells, which raises the question of the role of Pgp in the resistance of recurrent glioblastomas to imatinib.
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PMID:ABC transporters and the accumulation of imatinib and its active metabolite CGP74588 in rat C6 glioma cells. 1833 18

SUMMARY Sirodesmin PL is a non-host-selective phytotoxin produced by Leptosphaeria maculans, which causes blackleg disease of canola (Brassica napus). Previous studies have shown that sirodesmin PL biosynthesis involves a cluster of 18 co-regulated genes and that disruption of the two-module non-ribosomal peptide synthetase gene (sirP) in this cluster prevents the production of sirodesmin PL. Loss of sirodesmin PL did not affect the growth or fertility of the sirP mutant in vitro, but this mutant had less antibacterial and antifungal activity than the wild-type. When the sirP mutant was inoculated on to cotyledons of B. napus, it caused similar-sized lesions on cotyledons as the wild-type isolate, but subsequently caused fewer lesions and was half as effective as the wild-type in colonizing stems, as shown by quantitative PCR analyses. However, no significant difference was observed in size of lesions when either wild-type or mutant isolates were injected directly into the stem. The expression of two cluster genes, sirP and an ABC transporter, sirA, was studied in planta. Fungal isolates containing fusions of the green fluorescent protein gene with the promoters of these genes fluoresced after 10 days post-inoculation (dpi). Transcripts of sirP and sirA were detected after 11 dpi in cotyledons by reverse transcriptase PCR, and expression of both genes increased dramatically in stem tissue. This expression pattern was consistent with the distribution of sirodesmin PL in planta as revealed by mass spectrometry experiments.
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PMID:Production of the toxin sirodesmin PL by Leptosphaeria maculans during infection of Brassica napus. 2050 39

The marine fish pathogen Photobacterium damselae subsp. piscicida utilizes haem compounds as the sole iron source. In a previous work, we characterized a gene cluster with ten potential haem uptake and utilization genes. Two of these genes, hutC and hutD, which are iron-regulated, conform a putative inner membrane haem ABC transporter. In this study, we constructed an insertional mutant, leading to the inactivation of hutCD genes. Reverse transcriptase-PCR analyses demonstrated that an insertion between the hutB and hutC genes abolished transcription of the downstream hutC and hutD genes. The hutCD mutant was unable to utilize haem as the sole iron source, demonstrating that the putative ABC-transporter proteins HutC and HutD are essential for haem utilization as an iron source in P. damselae subsp. piscicida. In addition, reverse transcriptase-PCR assays conducted with RNA samples isolated from experimentally infected fish revealed the presence of hutCD transcripts. The results demonstrate for the first time that haem uptake genes of a fish pathogen are expressed during the infective process in fish.
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PMID:The ABC-transporter hutCD genes of Photobacterium damselae subsp. piscicida are essential for haem utilization as iron source and are expressed during infection in fish. 2056 Nov 40

Development of multidrug resistance (MDR) in cancer cells is associated with an overexpression of ATP-binding cassette proteins [e.g. P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP)] and with decreased chemotherapeutic agent-induced apoptosis. In this study, we investigated whether MDR in cancer cells was associated with altered expression of genes regulating apoptosis using a drug sensitive human myeloid leukemia cell line (HL60), and its MDR sublines, overexpressing MRP (HL60/AR) or P-gp (HL60/taxol). Expression of apoptotic Genes was examined at the protein level by flow cytometry and at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). We observed that the MDR cells either did not express or expressed a reduced level of the apoptosis promoters Fas, Bcl-x(s), and Bax, whereas expression of the apoptosis repressor Bcl-x, was increased. Both vincristine and anti-Fas monoclonal antibody induced apoptosis in HL60 cells but failed to do so in both MDR cell lines. These data suggest that acquired MDR in cancer cells, regardless of the type of overexpressed ABC transporter, may be associated with increased expression of antipeptidic genes and decreased expression of pro-apoptotic Genes.
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PMID:Altered expression of the genes regulating apoptosis in multidrug resistant human myeloid leukemia cell lines overexpressing MDR1 or MRP gene. 2152 88


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