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)

Human telomerase, a cellular reverse transcriptase (hTERT), is a nuclear ribonucleoprotein enzyme complex that catalyzes the synthesis and extension of telomeric DNA. This enzyme is specifically activated in most malignant tumors but is usually inactive in normal somatic cells, suggesting that telomerase plays an important role in cellular immortalization and tumorigenesis. Terminal maturation of tumor cells has been associated with the repression of telomerase activity. Using maturation-sensitive and -resistant NB4 cell lines, we analyzed the pattern of telomerase expression during the therapeutic treatment of acute promyelocytic leukemia (APL) by retinoids. Two pathways leading to the down-regulation of hTERT and telomerase activity were identified. The first pathway results in a rapid down-regulation of telomerase that is associated with retinoic acid receptor (RAR)-dependent maturation of NB4 cells. Furthermore, during NB4 cell maturation, obtained independently of RAR by retinoic X receptor (RXR)-specific agonists (rexinoids), no change in telomerase activity was observed, suggesting that hTERT regulation requires a specific signaling and occurs autonomously. A second pathway of hTERT regulation, identified in the RAR-responsive, maturation-resistant NB4-R1 cell line, results in a down-regulation of telomerase that develops slowly during two weeks of all-trans retinoic acid (ATRA) treatment. This pathway leads to telomere shortening, growth arrest, and cell death, all events that are overcome by ectopic expression of hTERT. These findings demonstrate a clear and full dissociation between the process of tumor cell maturation and the regulation of hTERT mRNA expression and telomerase activity by retinoids. We propose telomerase expression as an efficient and selective target of retinoids in the therapy of tumors.
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PMID:Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation. 1137 21

The measurement of Wilms' tumor gene (WT1) mRNA levels by reverse transcriptase-polymerase chain reaction (RT-PCR) is useful in detecting minimal residual disease (MRD) in leukemia patients. In the present study, we quantified the level of WT1 mRNA in the peripheral blood and bone marrow of patients with acute myelocytic leukemia (AML) at initial onset, remission and recurrence by the use of nucleic acid sequence based amplification (NASBA), and then ascertained the clinical usefulness of this method. At initial onset, the level of WT1 mRNA in the peripheral blood was above 10(3) copies/microgram and that in the bone marrow was above 10(4) copies/microgram. The level of WT1 mRNA was decreased in cases where therapy resulted in complete remission, but it was abnormally high in recurring cases. In AML (M3) patients, the relationship between the level of WT1 mRNA and the expression of the PML-retinoic acid alpha receptor (RAR alpha) gene, assessed by fluorescence in situ hybridization (FISH), was investigated. When leukemia was in remission hematologically, the PML-RAR alpha gene was negative and the level of WT1 mRNA decreased. These findings suggest that the quantification of WT1 gene expression by competitive NASBA is useful in assessing therapeutic effects and detecting MRD.
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PMID:Quantification of WT1 mRNA by competitive NASBA in AML patients. 1150 93

A microarray system is a powerful and very useful technology for analyzing the expression profile of thousands of genes. In this study, we made a cDNA microarray system carrying 2007 cDNAs obtained from primary neuroblastoma cDNA library and identified retinoic acid (RA)-regulated genes in a RTBM1 neuroblastoma cell line. We repeated independent hybridization experiment twice and found that 7 genes were up-regulated, and 5 genes were down-regulated on the cDNA microarray. The semi-quantitative reverse transcriptase (RT)-PCR analysis to confirm the results showed that 4 genes which included amyloid precursor-like protein 2 (APLP2), P311, dihydropyrimidinase related protein3 (DRP3) and RGP4 were up-regulated, while 2 genes, Id-2 and vimentin, were down-regulated. Thus, our neuroblastoma cDNA microarray system is useful to screen the neuronal differentiation- and growth-related genes regulated by RA with high efficiency.
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PMID:Detection of the retinoic acid-regulated genes in a RTBM1 neuroblastoma cell line using cDNA microarray. 1150 97

A population of cells derived from human and rodent bone marrow has been shown by several groups of investigators to give rise to glia and neuron-like cells. Here we show that human umbilical cord blood cells treated with retinoic acid (RA) and nerve growth factor (NGF) exhibited a change in phenotype and expressed molecular markers usually associated with neurons and glia. Musashi-1 and beta-tubulin III, proteins found in early neuronal development, were expressed in the induced cord blood cells. Other molecules associated with neurons in the literature, such as glypican 4 and pleiotrophin mRNA, were detected using DNA microarray analysis and confirmed independently with reverse transcriptase polymerase chain reaction (RT-PCR). Glial fibrillary acidic protein (GFAP) and its mRNA were also detected in both the induced and untreated cord blood cells. Umbilical cord blood appears to be more versatile than previously known and may have therapeutic potential for neuronal replacement or gene delivery in neurodegenerative diseases, trauma, and genetic disorders.
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PMID:Expression of neural markers in human umbilical cord blood. 1152 Jan 25

Acute promyelocytic leukemia (APL) is specifically associated with a reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of a fusion of the retinoic acid receptor-alpha (RARA) gene and the promyelocytic leukemia (PML) gene. However, there are several reports describing APL cases lacking the t(15; 17). Many such cases are those bearing variant translocations involving chromosomes 15 or 17, and those with no chromosomal aberrations have rarely been reported. We have studied a patient with APL showing an apparently normal karyotype which was confirmed by spectral karyotyping (SKY). A submicroscopic PML-RARA fusion was identified by reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescent in situ hybridization (FISH). All-trans retinoic acid (ATRA) was effective as the initial therapy for remission induction and as the reinduction therapy after a relapse. The present study shows the key role of the fusion of PML-RARA in the responsiveness to ATRA as well as in the leukemogenesis of APL.
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PMID:Acute promyelocytic leukemia with apparently normal karyotype: molecular findings and response to all-trans retinoic acid. 1169 3

We describe a variant form, French-American-British (FAB) M3v, of acute promyelocytic leukemia (APL; FAB M3) with atypical morphocytochemical features, immature antigens (CD34 and HLA-DR) and marked myelofibrosis (MF). Usual APL cells do not express CD34 or HLA-DR antigens. MF may be more frequently observed in patients with M3v expressing CD34 and HLA-DR antigens than in patients with M3 lacking these antigens. Despite marked MF, recovery from the hypoplastic phase in the case we described was not delayed after remission induction chemotherapy consisting of enocitabine, 200 mg/mi2 intravenously; 6-mercaptopurine, 70 mg/m2 orally for 10 days; daunorubicin 40 mg/m2 intravenously for 4 days; and all-trans retinoic acid 45 mg/M2 orally between days 20 and 33. The promyelocytic leukemia-retinoic-acid receptor (PML-RAR) alpha fusion transcript, according to reverse transcriptase-polymerase chain reaction (RT-PCR), became negative in the bone marrow after the first course of consolidation chemotherapy. Autologous peripheral blood stem cell transplantation (autoPBSCT) was carried out after 3 courses of consolidation chemotherapy. There were no specific complications based on MF throughout the clinical course, including engraftment in autoPBSCT. The patient has been without MF and in molecular remission, defined as disappearance of the PML-RAR alpha fusion transcript according to RT-PCR, for 21 months. Longer follow-up will clarify the effects of autoPBSCT on prognosis in APL with MF.
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PMID:A variant form of acute promyelocytic leukemia with marked myelofibrosis. 1172 70

Telomerase, a ribonucleoprotein complex of hTERT, hTR, and TP1, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). This study used our in vitro human cervical multistep carcinogenesis/MDR model system in which normal human ectocervical and endocervical (HEN) cells were immortalized by HPV18 or 16, respectively, and subsequently transformed. The first evidence was found that immortalization and telomerase activation were correlated with increased expression specifically of two of the hTERT alternatively spliced mRNAs, one encoding wild-type protein containing the full-length functional reverse transcriptase (RT) region and one encoding a defective RT protein. Expression of neither hTERT mRNA containing full-length functional or defective RT motif was affected by transformation/MDR. All-trans-retinoic acid (ATRA) treatment of HPV-immortalized HEN-16-2 cells and transformed/MDR HEN-16-2/CDDP cells inhibited telomerase activity and downregulated expression of hTERT mRNAs containing full-length functional and a defective RT motif, but there were no changes in hTR and TP1 expression. Moreover, ATRA inhibited cell growth rate of HEN-16-2 and HEN-16-2/CDDP cells equally. These results provided the first evidence that ATRA equally in both immortalized and transformed/MDR cell lines inhibits telomerase activity and downregulates expression, but not splicing, of hTERT, and this is correlated with cell growth rate inhibition; the potential is implicated for applying ATRA to hTERT-targeted treatment of cervical cell carcinogenesis/MDR.
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PMID:Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT: correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model. 1177 43

We analyzed the expression of neuronal regulatory genes Mash-1 and c-ret by immunohistochemistry and reverse transcriptase-polymerase chain reaction in the developing heart of rat embryos following exogenous retinoic acid (RA) treatment of the pregnant dams. On E12, expression of Mash-1 and c-ret was confined to cells migrating via the common cardinal vein. On E16.5, Mash-1 and c-ret expression were restricted to cardiac ganglia around the great vessels and posterior atrial wall. While Mash-1 expression was down-regulated at birth, that of c-Ret was maintained. RA-treated hearts showed a down-regulation of both Mash-1 and c-Ret at the mRNA as well as at the protein level on E16.5. The present results show that differentiation of cardiac ganglionic cells is affected after RA treatment, by the down-regulation of Mash-1 and c-Ret.
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PMID:Retinoic acid influences the expression of the neuronal regulatory genes Mash-1 and c-ret in the developing rat heart. 1180 16

Loss of the inhibition of apoptosis is important in leukemogenesis and may influence the prognosis. Survivin is an inhibitor of apoptosis that shows selective expression during fetal development and in human malignancies. Survivin expression was examined in human leukemias using the reverse transcriptase-polymerase chain reaction. Survivin gene expression was detected in 17 of 31 patients with acute myelocytic leukemia and 11 of 16 patients with acute lymphocytic leukemia but was not identified in normal bone marrow cells. Survivin expression was lower in patients with M3 acute myelocytic leukemia than in patients with other types of acute leukemia. Survivin was not detected in the chronic phase of chronic myelocytic leukemia but was observed in 5 of 7 patients with chronic myelocytic leukemia in blastic crisis. These findings suggest a relationship between survivin gene expression and hematopoietic cell differentiation. In fact, survivin gene expression was down-regulated during the differentiation of HL-60 cells after treatment with dimethyl sulfoxide or all-trans-retinoic acid. Moreover, the disease-free survival rates of patients with survivin expression were lower than in patients without survivin expression. Accordingly, survivin may have a role in leukemogenesis as well as in other malignancies. Detecting survivin may also provide prognostic information.
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PMID:Expression of the antiapoptosis gene survivin in human leukemia. 1193 62

Glucuronidation, mediated by UDP-glucuronosyltransferases (UGTs), affects the actions and disposition of diverse endo- and xenobiotics. In the case of catecholestrogens (CEs), glucuronidation is likely to block their oxidation to quinone estrogens that are the putative mediators of CEs' actions as initiators of cancers. The goal of this study was to determine whether UGT2B7, the isoenzyme with a high affinity for 4-hydroxyestrone, is expressed in human breast parenchyma. Glucuronidation of 4-hydroxyestrone has relevance to breast carcinogenesis because quinone metabolites of 4-hydroxylated CEs can form potentially mutagenic depurinating DNA adducts, and because in breast tissue estrone is likely to be the predominant estrogen available for 4-hydroxylation. Using reverse transcriptase-polymerase chain reaction, immunocytochemistry, immunoblot analyses, and assays of glucuronidation of 4-hydroxyestrone, we show that UGT2B7 is expressed in human mammary epithelium, and that its expression is dramatically reduced in invasive breast cancers. In many in situ carcinomas, however, 4-hydroxyestrone immunostaining was not only preserved but even more intense than in normal mammary epithelium. The finding of reduced UGT2B7 protein and glucuronidation of 4-hydroxyestrone in invasive cancers suggests a tumor-suppressor function for the enzyme. Recent identification of all-trans retinoic acid as a substrate of UGT2B7 suggests that this function includes the generation of retinoyl-beta-glucuronide, a potent mediator of actions of retinoids important for maintaining epithelia in a differentiated state. Current knowledge does not provide any ready explanation for the apparent increase in UGT2B7 expression in carcinomas in situ. However, this finding, together with reduced immunostaining at loci showing breach of the basement membrane (microinvasion), suggests involvement of UGT2B7-catalyzed reaction(s) in protection against invasion of surrounding tissue by cancer cells.
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PMID:Expression of UGT2B7, a UDP-glucuronosyltransferase implicated in the metabolism of 4-hydroxyestrone and all-trans retinoic acid, in normal human breast parenchyma and in invasive and in situ breast cancers. 1194 30


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