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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.
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PMID:Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors. 1054 87

Human salivary gland adenocarcinoma cells (HSG) express nuclear receptors, all-trans-retinoic acid (at-RA) receptors (RARs), and retinoid X/9-cis-retinoic acid (9-c-RA) receptors (RXRs). In order to investigate whether the endogenous RARs or RXRs of HSG cells can induce transcription activation, the thymidine kinase promoter (TK)-driven luciferase reporter gene containing the retinoic acid response element (RARE), of RARbeta, betaRARE2-TK-Luc, was transfected into HSG cells and ligand-dependent transcription activation was examined. Luciferase activity of cell lysate increased by the treatment with either at-RA or 9-c-RA. Co-transfection of RARalpha and (or) RXRalpha-expression plasmids with the reporter gene enhanced the luciferase activity, suggesting that endogenous RARs and RXRs work as ligand-dependent transfactors in HSG cells. Reverse transcriptase - polymerase chain reaction analysis revealed that HSG cells express chicken ovalbumin upstream promoter - transcription factor I (COUP-TFI). Co-transfection of COUP-TFI-expression plasmid suppressed the at-RA-induced transcription activation of the reporter gene. Similar results were shown using a chromatin-integrated reporter gene system, using a stably transfected beta-RARE2-TK-beta-galactosidase (beta-Gal) reporter gene. The at-RA-dependent increase in the beta-Gal expression was completely inhibited by COUP-TFI. The transfection of antisense oligonucleotide of COUP-TFI squelched the RA-dependent growth inhibition induced by RAR-RXR heterodimers. Conclusively, RARs and RXRs of HSG cells are functional and play roles as transactivators in at-RA-sensitive processes such as the proliferation or differentiation of cells. COUP-TFI very likely regulates these processes by repressing the functions of these transactivators.
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PMID:Inhibition of retinoic acid-inducible transcription by COUP-TFI in human salivary gland adenocarcinoma cell line HSG. 1066 29

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

Activation of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription in response to all-trans-retinoic acid (RA) or a glucocorticoid such as dexamethasone (Dex) requires a distinct arrangement of DNA-response elements and their cognate transcription activators on the gene promoter. Two of the accessory factor-binding elements involved in the Dex response (gAF1 and gAF3) coincide with the DNA-response elements involved in the RA response. We demonstrate here that the combination of Dex/RA has a synergistic effect on endogenous PEPCK gene expression in rat hepatocytes and H4IIE hepatoma cells. Reporter gene studies show that the gAF3 element and one of the two glucocorticoid receptor-binding elements (GR1) are most important for this effect. Chromatin immunoprecipitation assays revealed that when H4IIE cells were treated with Dex/RA, ligand-activated retinoic acid receptors (retinoic acid receptor/retinoid X receptor) and glucocorticoid receptors are recruited to this gene promoter, as are the transcription coregulators p300, CREB-binding protein, p/CIP, and SRC-1. Notably, the recruitment of p300 and RNA polymerase II to the PEPCK promoter is increased by the combined Dex/RA treatment compared with Dex or RA treatment alone. The functional importance of p300 in the Dex/RA response is illustrated by the observation that selective reduction of this coactivator, but not that of CREB-binding protein, abolishes the synergistic effect in H4IIE cells.
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PMID:The synergistic effect of dexamethasone and all-trans-retinoic acid on hepatic phosphoenolpyruvate carboxykinase gene expression involves the coactivator p300. 1516 31

Chronic skin disorders that require long-term treatment with corticosteroids, such as vitiligo, may use a combination of topical corticosteroids and topical all-trans-retinoic acid (ATRA) to prevent corticosteroid-induced skin atrophy. Besides protecting against the side effects of corticosteroids, ATRA produces a better clinical outcome in some patients. This study examined whether ATRA influences the expression of mRNAs responsible for the clinical correlation. Differential display was performed using kits incorporating an annealing control primer. Epidermis from suction blisters taken from six patients diagnosed with a generalized type of vitiligo, who were included in a placebo-controlled paired-comparison left-right study using ATRA and vehicle for 3-6 months, were used. Ten differentially expressed mRNAs were identified in those six patients. Expression levels were restored to normal particularly in four types of mRNAs, which were matched with sequences encoding eukaryotic translation initiation factor 4A1 (eIF4A1), ribosomal protein L13, mediator of RNA polymerase to transcription (MRT) and ribosomal phosphoprotein PO. Of those mRNAs, the level of eIF4A1 mRNA showed a clinical correlation; The expression of eIF4A1 mRNA, examined by real-time PCR, was elevated in four patients who showed a favorable clinical response to ATRA, whereas no change or a decrease occurred in three patients whose clinical responses did not differ between ATRA and vehicle treatment. The eIF4A1 protein expression from the other two patients, one of them with a favorable response to ATRA, also showed a clinical correlation. Therefore, eIF4A1 mRNA may be an important gene related to ATRA effects, although further studies are required.
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PMID:All trans-retinoic acid (ATRA) elevated eukaryotic translation initiation factor 4A1 (eIF4A1) mRNA in ATRA-responsive vitiliginous epidermis. 1554 Oct 24

The C-terminal domain (CTD) of the large subunit of RNA polymerase II is a platform for mRNA processing factors and links gene transcription to mRNA capping, splicing and polyadenylation. Pcf11, an essential component of the mRNA cleavage factor IA, contains a CTD-interaction domain that binds in a phospho-dependent manner to the heptad repeats within the RNA polymerase II CTD. We show here that the phosphorylated CTD exists as a dynamic disordered ensemble in solution and, by induced fit, it assumes a structured conformation when bound to Pcf11. In addition, we detected cis-trans populations for the CTD prolines, and found that only the all-trans form is selected for binding. These data suggest that the recognition of the CTD is regulated by independent site-specific modifications (phosphorylation and proline cis-trans isomerization) and, probably, by the local concentration of suitable binding sites.
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PMID:Key features of the interaction between Pcf11 CID and RNA polymerase II CTD. 1570 66

Hyaluronan is an abundant and rapidly turned over matrix molecule between the vital cell layers of the epidermis and subject to large concentration changes associated with keratinocyte proliferation, migration, and differentiation induced by paracrine and endocrine factors like epidermal growth factor (EGF) and all-trans-retinoic acid (RA). We found that in REK cells EGF and all-trans-RA up-regulated hyaluronan synthase 2 (Has2) gene expression within 2 h 4-fold each and in HaCaT human immortal keratinocytes 8- and 33-fold, respectively. The first 10 kb of the human Has2 promoter were scanned in silico and in vitro for potential response elements of signal transducer and activator of transcription (STAT) or RA receptor (RAR) proteins. We identified a STAT-response element in the proximal promoter region and confirmed its functionality in response to EGF by chromatin immunoprecipitation (ChIP) assays. Direct in vitro binding of RARs to four RARE candidates within the Has2 promoter could not be observed at stringent gel shift conditions, but reporter gene assays demonstrated functionality of a complex of two of these RAREs located approximately 1200 bp upstream of the transcription start site. Moreover, ChIP assays using antibodies against nine nuclear proteins monitored all-trans-RA-dependent binding of RAR, retinoid X receptor, mediator protein, and RNA polymerase II and also histone 4 acetylation to a promoter region containing the complex RARE. Taken together, the human Has2 gene is a potent primary EGF and all-trans-RA responding gene with a complex regulation.
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PMID:The human hyaluronan synthase 2 gene is a primary retinoic acid and epidermal growth factor responding gene. 1572 43

The EVI1 gene plays important roles in development and leukemogenesis. Recently, human EVI1 has been shown to give rise to at least six different mRNA variants with alternative 5'-ends, only some of which are conserved in mice. In order to gain a basic understanding of the regulation and potential biological importance of these alternative transcripts, we confirmed their expression by Northern blot, and, using real time quantitative RT-PCR, compared their abundance and stability under different conditions. The general expression patterns of the EVI1 5'-end variants in a panel of 20 human tissues were similar, but particularly high or low levels of some of them were noted in certain tissues. Pronounced differences in the expression of the 5'-end variants were noted in response to all-trans retinoic acid: in a human teratocarcinoma cell line, only the EVI1 transcript variants containing alternative exons 1a and 1b were upregulated in response to this agent. This induction required transcriptional activity of RNA polymerase, but was also associated with a substantial increase in the stability of these mRNA variants.
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PMID:Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends. 1601 22

Hyaluronan (HA) is a polysaccharide of the vertebrate extracellular matrix, produced by three related HA synthases (HASs) that influence numerous physiological processes. We screened the first 2250 bp of the HAS2 promoter for transcription factor response elements (REs) in silico and found 1 cluster of 2 retinoic acid (RA) REs, 3 discrete NF-kappaB factors, and 12 Sp1 REs. In parallel, we scanned nine overlapping promoter regions in HaCaT human immortalized keratinocytes using chromatin immunoprecipitation assays to identify binding of mediator, coactivator, and corepressor proteins and Sp1 transcription factor in response to all-trans-RA and tumor necrosis factor-alpha (TNF-alpha). We found that all-trans-RA modulated the binding of the RA receptor and several coregulators to the region containing the RARE cluster at position -1230. The importance of this region is supported in reporter gene assays by the all-trans-RA induction of the respective promoter region. Similarly, we showed by chromatin immunoprecipitation assays as well as by gel-shift assays with nuclear extracts that TNF-alpha induced NF-kappaB binding to regions at positions -380, -1420, and -1890, demonstrated its association with RNA polymerase II and cofactor proteins, and confirmed the functionality of the respective promoter regions in vivo. These findings partially explain the induction of HAS2 mRNA by all-trans-RA and TNF-alpha and provide an example how the action of different transcription factor families can use the same cofactors.
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PMID:Integration of the activation of the human hyaluronan synthase 2 gene promoter by common cofactors of the transcription factors retinoic acid receptor and nuclear factor kappaB. 1730 35

A 18-year-old man was diagnosed with acute promyelocytic leukemia (APL). The conventional cytogenetic analysis revealed normal karyotype 46, XY, t(15; 17). Reverse transcriptase polymerase chain reaction (RTPCR) identified PML-RARa chimeric transcripts. Complete remission (CR) was attained with 3 induction courses of Ara-C, daunorubicin and all-trans retinoic acid (ATRA). Three years later the patient relapsed. The blasts in bone marrow aspirate at relapse had AML-M3 morphology, and RT-PCR was positive for PML-RARa transcripts. The patient was treated with ATRA and daunorubicin without success. Two months later the blasts in bone marrow aspirate showed AML-M2 morphology, the karyotype was 47, XY, +8 and RT-PCR revealed the presence of AML1-ETO transcripts and absence of PML-RARa transcripts. The patient attained second CR with 3 induction courses -a course with Ara-C and daunorubicin and 2 courses with idarubicin, Ara-C and etoposide.
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PMID:Clonal heterogeneity in a patient with acute promyelocytic leukemia. 1741 15


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