Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P23193 (transcription elongation factor)
 739 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3 x 60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.
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PMID:Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study). 1525 64

Positive transcription elongation factor b (P-TEFb) stimulates the transition from transcription initiation to productive elongation by phosphorylation of the C-terminal domain of RNA polymerase II. P-TEFb consists of the cyclin-dependent kinase Cdk9 and a T-type cyclin and is regulated by the small nuclear RNA 7SK and the coupling protein Hexim1 or Hexim2. In this study, we analyzed the tripartite protein-RNA complex formation between Hexim, Cyclin T and 7SK snRNA. Using isothermal titration calorimetry, we observed higher affinities for Cyclin T1-Hexim1 and Cyclin T2-Hexim2 complex formations compared with the interactions in reverse. Importin alpha, which is part of the Ran-mediated nuclear import pathway, bound Hexim1 and Hexim2 with dissociation constants of 2.0 and 0.5 muM, respectively. Furthermore, tripartite complex formations between Cyclin T, Hexim and Importin alpha showed the suitability of a collaborative nuclear import pathway for Cyclin T. Electrophoretic mobility shift assays using radioactively labelled full-length 7SK snRNA revealed a tight association of the RNA to Cyclin T1-Hexim1 with dissociation constants lower than 0.3 muM. Similar binding affinities were recorded for both Hexim orthologues to a 66-mer double-stranded 5' hairpin loop encompassing nucleotides 23-88 of 7SK, while a 39-mer fragment, resulting from different RNA folding predictions, did not bind as tightly. These results provide the molecular basis for the generation of a core complex for the inhibition of P-TEFb.
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PMID:Specificity of Hexim1 and Hexim2 complex formation with cyclin T1/T2, importin alpha and 7SK snRNA. 1988 59