dichlororibofuranosylbenzimidazole

Summary

Summary: An RNA polymerase II transcriptional inhibitor. This compound terminates transcription prematurely by selective inhibition of RNA synthesis. It is used in research to study underlying mechanisms of cellular regulation.

Top Publications

  1. Marshall N, Price D. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem. 1995;270:12335-8 pubmed
    ..Using a P-TEFb-dependent transcription system, we show that P-TEFb acts after initiation and is the limiting factor in the production of long run-off transcripts. ..
  2. Stoimenov I, Gottipati P, Schultz N, Helleday T. Transcription inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) causes DNA damage and triggers homologous recombination repair in mammalian cells. Mutat Res. 2011;706:1-6 pubmed publisher
    ..In conclusion, we show that DRB-induced transcription inhibition is associated with the formation of a lesion that triggers RAD51-dependent homologous recombination repair, required for survival under transcriptional stress. ..
  3. Luecke H, Yamamoto K. The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoter-specific transcriptional repression. Genes Dev. 2005;19:1116-27 pubmed
    ..Thus, GR accomplishes selective repression by targeting promoter-specific components of NFkappaB regulatory complexes. ..
  4. Custodio N, Carmo Fonseca M, Geraghty F, Pereira H, Grosveld F, Antoniou M. Inefficient processing impairs release of RNA from the site of transcription. EMBO J. 1999;18:2855-66 pubmed
    ..Therefore, 3' end processing and splicing appear to be rate limiting for release of mRNA from the site of transcription. ..
  5. Ivanov D, Kwak Y, Guo J, Gaynor R. Domains in the SPT5 protein that modulate its transcriptional regulatory properties. Mol Cell Biol. 2000;20:2970-83 pubmed
    ..These results suggest that C-terminal repeats in SPT5, like those in the RNA polymerase II C-terminal domain, are sites for P-TEFb phosphorylation and function in modulating its transcriptional elongation properties. ..
  6. Kim Y, Bourgeois C, Isel C, Churcher M, Karn J. Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. Mol Cell Biol. 2002;22:4622-37 pubmed
    ..We conclude that phosphorylation of the RNA polymerase II CTD by CDK9 enhances transcription elongation directly. ..
  7. Muller W, Walker D, Hager G, McNally J. Large-scale chromatin decondensation and recondensation regulated by transcription from a natural promoter. J Cell Biol. 2001;154:33-48 pubmed
    ..They also support fiber-packing models of higher order structure and suggest that transcription from a natural promoter may occur at much higher DNA-packing densities than reported previously. ..
  8. O Hagan H, Ljungman M. Phosphorylation and nuclear accumulation are distinct events contributing to the activation of p53. Mutat Res. 2004;546:7-15 pubmed
  9. Baumli S, Endicott J, Johnson L. Halogen bonds form the basis for selective P-TEFb inhibition by DRB. Chem Biol. 2010;17:931-6 pubmed publisher
    ..These results open the possibility to exploit halogen atoms in inhibitor design to specifically target Cdk9. ..

More Information

Publications62

  1. MacCallum D, Melville J, Frame S, Watt K, Anderson S, Gianella Borradori A, et al. Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005;65:5399-407 pubmed
    ..This study provides the scientific rationale for the clinical development of seliciclib for the treatment of multiple myeloma. ..
  2. Louvet E, Junéra H, Le Panse S, Hernandez Verdun D. Dynamics and compartmentation of the nucleolar processing machinery. Exp Cell Res. 2005;304:457-70 pubmed
    ..This suggests that protein dynamics and interactions, and not only their processing activity, determine compartmentation of the nucleolar machineries. ..
  3. Kimura H, Cook P. Kinetics of core histones in living human cells: little exchange of H3 and H4 and some rapid exchange of H2B. J Cell Biol. 2001;153:1341-53 pubmed
    ..These results reveal that the inner core of the nucleosome is very stable, whereas H2B on the surface of active nucleosomes exchanges continually. ..
  4. Wada T, Takagi T, Yamaguchi Y, Ferdous A, Imai T, Hirose S, et al. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 1998;12:343-56 pubmed
    ..The combination of biochemical studies on DSIF and genetic analysis of Spt4 and Spt5 in yeast, also in this issue, indicates that DSIF associates with RNA Pol II and regulates its processivity in vitro and in vivo. ..
  5. Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 1998;17:7395-403 pubmed
    ..Taken together, this study reveals a molecular basis for DRB action and suggests that P-TEFb stimulates elongation by alleviating the negative action of DSIF. ..
  6. Yamaguchi Y, Takagi T, Wada T, Yano K, Furuya A, Sugimoto S, et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell. 1999;97:41-51 pubmed
    ..This study reveals a molecular mechanism for DRB action and a regulatory network of positive and negative elongation factors. ..
  7. Zhou M, Halanski M, Radonovich M, Kashanchi F, Peng J, Price D, et al. Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription. Mol Cell Biol. 2000;20:5077-86 pubmed
    ..These studies suggest that the ability of Tat to increase transcriptional elongation may be due to its ability to modify the substrate specificity of the CDK9 complex. ..
  8. Lever M, Th ng J, Sun X, Hendzel M. Rapid exchange of histone H1.1 on chromatin in living human cells. Nature. 2000;408:873-6 pubmed
    ..Our results show that histone H1 exchange in vivo is rapid, occurs through a soluble intermediate, and is modulated by the phosphorylation of a protein or proteins as yet to be determined. ..
  9. Barboric M, Nissen R, Kanazawa S, Jabrane Ferrat N, Peterlin B. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001;8:327-37 pubmed
    ..Remarkably, DRB inhibition sensitized cells to TNF-alpha-induced apoptosis. Thus, NF-kappaB requires P-TEFb to stimulate the elongation of transcription and P-TEFb plays an unexpected role in regulating apoptosis. ..
  10. Hu Y, Chen S, Chen H, Pan H. Casein kinase II inhibition reverses pain hypersensitivity and potentiated spinal N-methyl-D-aspartate receptor activity caused by calcineurin inhibitor. J Pharmacol Exp Ther. 2014;349:239-47 pubmed publisher
    ..CK2 inhibitors may represent a new therapeutic option for the treatment of CIPS. ..
  11. Jacobs E, Ogiwara I, Weiner A. Role of the C-terminal domain of RNA polymerase II in U2 snRNA transcription and 3' processing. Mol Cell Biol. 2004;24:846-55 pubmed
    ..We predict that snRNA promoters recruit factors including a CTD kinase(s) whose snRNA-specific phosphorylation pattern recruits factors required for promoter-coupled 3' end formation. ..
  12. Igaz L, Vianna M, Medina J, Izquierdo I. Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning. J Neurosci. 2002;22:6781-9 pubmed
  13. Patel N, Yamamoto M, Illingworth P, Mancu D, Mebert K, Chappell D, et al. Phosphoinositide 3-kinase mediates protein kinase C beta II mRNA destabilization in rat A10 smooth muscle cell cultures exposed to high glucose. Arch Biochem Biophys. 2002;403:111-20 pubmed
    ..In these cells, high-glucose concentrations activated a metabolically linked signaling pathway independent of glucose metabolism to regulate mRNA processing. ..
  14. Ristaldi M, Drabek D, Gribnau J, Poddie D, Yannoutsous N, Cao A, et al. The role of the -50 region of the human gamma-globin gene in switching. EMBO J. 2001;20:5242-9 pubmed
  15. Park H, Lee S, Lee J, Kim Y, Bae Y, Park J. Phosphorylation of the leucocyte NADPH oxidase subunit p47(phox) by casein kinase 2: conformation-dependent phosphorylation and modulation of oxidase activity. Biochem J. 2001;358:783-90 pubmed
    ..Taken together, we propose that CK2 is the p47(phox) kinase, and that phosphorylation of p47(phox) by CK2 regulates the deactivation of NADPH oxidase. ..
  16. Sahmi M, Nicola E, Price C. Hormonal regulation of cytochrome P450 aromatase mRNA stability in non-luteinizing bovine granulosa cells in vitro. J Endocrinol. 2006;190:107-15 pubmed
    ..05) that in FSH-stimulated cells. We conclude that bovine Cyp19 mRNA is very labile under physiological conditions, and that Cyp19 expression is under hormonal control at a post-transcriptional level. ..
  17. Guo C, Savage L, Sarge K, Park Sarge O. Gonadotropins decrease estrogen receptor-beta messenger ribonucleic acid stability in rat granulosa cells. Endocrinology. 2001;142:2230-7 pubmed
    ..Taken together, our results demonstrate that LH decreases ERbeta mRNA expression, predominantly at the posttranscriptional level, in a cycloheximide-sensitive manner. ..
  18. Kozyrev S, Nikitin V. Involvement of translation and transcription processes into neurophysiological mechanisms of long-term memory reconsolidation. Bull Exp Biol Med. 2013;154:584-7 pubmed
    ..The study suggests that the proteins translated from previously synthesized and stored mRNA were involved in the mechanisms of reconsolidation of the memory responsible for conditioned taste aversion. ..
  19. Gargano B, Amente S, Majello B, Lania L. P-TEFb is a crucial co-factor for Myc transactivation. Cell Cycle. 2007;6:2031-7 pubmed
    ..These results indicate that P-TEFb is recruited in vivo to Myc-target promoters and CDK9 activity is an important step for Myc-dependent stimulation of responsive genes. ..
  20. Pautz A, Linker K, Hubrich T, Korhonen R, Altenhöfer S, Kleinert H. The polypyrimidine tract-binding protein (PTB) is involved in the post-transcriptional regulation of human inducible nitric oxide synthase expression. J Biol Chem. 2006;281:32294-302 pubmed
    ..The underlying mechanism is based on a modulation of iNOS mRNA stability. In summary, human iNOS is the first example of a human pro-inflammatory gene regulated by PTB on the level of mRNA stability. ..
  21. Harayama H, Murase T, Miyake M. A cyclic adenosine 3',5'-monophosphate stimulates phospholipase Cgamma1-calcium signaling via the activation of tyrosine kinase in boar spermatozoa. J Androl. 2005;26:732-40 pubmed
  22. Joannard F, Rissel M, Gilot D, Anderson A, Orfila Lefeuvre L, Guillouzo A, et al. Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes. Toxicol Lett. 2006;161:61-72 pubmed
  23. Onorato T, Chakraborty S, Haldar D. Phosphorylation of rat liver mitochondrial glycerol-3-phosphate acyltransferase by casein kinase 2. J Biol Chem. 2005;280:19527-34 pubmed
    ..Collectively, these data suggest that CK2 phosphorylates mtGAT. The impact of our results in the regulation of mtGAT and other anabolic processes is discussed. ..
  24. Liu X, Liang N, Liu W, She J, Mo L. [Inhibitory effect and kinetic analysis of sodium quercetin-7,4'-disulphate on recombinant human protein kinase CK2 holoenzyme]. Yao Xue Xue Bao. 2002;37:165-8 pubmed
    ..SQDS is a potent inhibitor of protein kinase CK2. This study provide experimental basis for the development of more effective inhibitors of CK2 and for clinical application of SQDS in the future. ..
  25. Dorighi K, Tamkun J. The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila. Development. 2013;140:4182-92 pubmed publisher
    ..These and other findings suggest that KIS antagonizes Polycomb group repression by facilitating ASH1-dependent H3K36 dimethylation. ..
  26. Murase T, El Kon I, Harayama H, Mukoujima K, Takasu M, Sakai K. Hyperactivated motility of frozen-thawed spermatozoa from fertile and subfertile Japanese black bulls induced by cyclic adenosine 3',5'-monophosphate analogue, cBiMPS. J Reprod Dev. 2010;56:36-40 pubmed
  27. Kimura R, Matsuki N. Protein kinase CK2 modulates synaptic plasticity by modification of synaptic NMDA receptors in the hippocampus. J Physiol. 2008;586:3195-206 pubmed publisher
    ..These findings support the latter hypothesis, that CK2 selectively affects LTP by selective modification of synaptic NMDA receptors in a receptor-location-specific manner. ..
  28. Kimura H, Sugaya K, Cook P. The transcription cycle of RNA polymerase II in living cells. J Cell Biol. 2002;159:777-82 pubmed
    ..Then, most expressed transcription units would spend significant times unassociated with engaged polymerases. ..
  29. Cammarota M, Bevilaqua L, Kerr D, Medina J, Izquierdo I. Inhibition of mRNA and protein synthesis in the CA1 region of the dorsal hippocampus blocks reinstallment of an extinguished conditioned fear response. J Neurosci. 2003;23:737-41 pubmed
  30. Yagi K, Tsuji K, Nifuji A, Shinomiya K, Nakashima K, DeCrombrugghe B, et al. Bone morphogenetic protein-2 enhances osterix gene expression in chondrocytes. J Cell Biochem. 2003;88:1077-83 pubmed
    ..These results indicated that osterix gene is expressed in the primary cultures of chondrocytes and its expression is under the control of BMP-2. ..
  31. Steveson T, Zhao G, Keutmann H, Mains R, Eipper B. Access of a membrane protein to secretory granules is facilitated by phosphorylation. J Biol Chem. 2001;276:40326-37 pubmed
    ..The increased ability of solubilized PAM-1 TS/DD to aggregate at neutral pH may play an important role in its altered trafficking. ..
  32. Edwards D, Parfett C, Denhardt D. Transcriptional regulation of two serum-induced RNAs in mouse fibroblasts: equivalence of one species to B2 repetitive elements. Mol Cell Biol. 1985;5:3280-8 pubmed
    ..Sequence analysis of the 49C8 cDNA clone showed greater than 90% homology of a large portion to a consensus rodent B2 repetitive element. ..
  33. Wu X, Lei X, Fu Z. Rabies virus nucleoprotein is phosphorylated by cellular casein kinase II. Biochem Biophys Res Commun. 2003;304:333-8 pubmed
    ..Thus, our data demonstrate that cellular CK-II phosphorylates rabies virus N. ..
  34. Lawson K, Larentowicz L, Laury Kleintop L, Gilmour S. B23 is a downstream target of polyamine-modulated CK2. Mol Cell Biochem. 2005;274:103-14 pubmed
    ..These data suggest that B23 may be a downstream effector of polyamines via phosphorylation by the protein kinase CK2. ..
  35. da Silva W, Bonini J, Bevilaqua L, Medina J, Izquierdo I, Cammarota M. Inhibition of mRNA synthesis in the hippocampus impairs consolidation and reconsolidation of spatial memory. Hippocampus. 2008;18:29-39 pubmed
  36. Mohapatra S, Chu B, Zhao X, Djeu J, Cheng J, Pledger W. Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors. Int J Biochem Cell Biol. 2009;41:595-602 pubmed publisher
    ..Collectively, our data show apoptosis of prostate cancer cells by a drug combination and identify Bax activation as a basis of cooperation. ..
  37. Sosroseno W, Sugiatno E. Cyclic-AMP-dependent proliferation of a human osteoblast cell line (HOS cells) induced by hydroxyapatite: effect of exogenous nitric oxide. Acta Biomed. 2008;79:110-6 pubmed
  38. Lee J, Yang Y, Liang F, Gough D, Levy D, Sehgal P. Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am J Physiol Cell Physiol. 2012;302:C804-20 pubmed publisher
    ..These data provide evidence of a STAT-family protein regulating the structure of a cytoplasmic organelle and implicate this mechanism in the pathogenesis of a human disease. ..
  39. Hung M, Tsai L, Lin Y, Chen Y, Chang G, Chang T. Differential regulation of placental and germ cell alkaline phosphatases by glucocorticoid and sodium butyrate in human gastric carcinoma cell line TMK-1. Arch Biochem Biophys. 2001;388:45-54 pubmed
    ..Taken together, this study indicates that the expression of PAP and GCAP isozymes have specific regulatory mechanisms that can be differentially controlled by signals including glucocorticoid and NaBu. ..
  40. Dolan B, Knowlton J, David A, Bennink J, Yewdell J. RNA polymerase II inhibitors dissociate antigenic peptide generation from normal viral protein synthesis: a role for nuclear translation in defective ribosomal product synthesis?. J Immunol. 2010;185:6728-33 pubmed publisher
    ..These data support the idea that Ag processing uses compartmentalized translation, perhaps even in the nucleus itself, to increase the efficiency of the generation of class I peptide ligands. ..
  41. Solntseva S, Nikitin V. Conditioned food aversion reconsolidation in snails is impaired by translation inhibitors but not by transcription inhibitors. Brain Res. 2012;1467:42-7 pubmed publisher
    ..Our present findings indicate that proteins synthesized from preexisting mRNA that is transcribed during learning and stored in a silent state may be involved in the mechanisms of conditioned food aversion reconsolidation. ..
  42. Becker M, Baumann C, John S, Walker D, Vigneron M, McNally J, et al. Dynamic behavior of transcription factors on a natural promoter in living cells. EMBO Rep. 2002;3:1188-94 pubmed
    ..Our results indicate that GR and GRIP-1 as components of the activating complex are in a dynamic equilibrium with the promoter, and must return to the template many times during the course of transcriptional activation. ..
  43. Motzkus D, Maronde E, Grunenberg U, Lee C, Forssmann W, Albrecht U. The human PER1 gene is transcriptionally regulated by multiple signaling pathways. FEBS Lett. 2000;486:315-9 pubmed
    ..This regulation of hPER1 appears to be significant for rapid adaptation to changing environmental conditions. ..
  44. Ye Z, Li D, Li L, Pan H. Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension. J Neurosci. 2011;31:8271-9 pubmed publisher
    ..Our findings suggest that augmented CK2 activity critically contributes to increased presynaptic and postsynaptic NMDAR activity in the PVN and elevated sympathetic vasomotor tone in essential hypertension. ..
  45. Stoimenov I, Schultz N, Gottipati P, Helleday T. Transcription inhibition by DRB potentiates recombinational repair of UV lesions in mammalian cells. PLoS ONE. 2011;6:e19492 pubmed publisher
    ..Thus, increased RAD51 foci formation correlates with increased cell death, suggesting the existence of a futile HR repair of UV-induced DSBs which is linked to transcription inhibition. ..
  46. Derebecka Holysz N, Lehmann T, Holysz M, Trzeciak W. TGF-beta inhibits CYP17 transcription in H295R cells acting via activin receptor-like kinase 5. Endocr Res. 2009;34:68-79 pubmed publisher
    ..We concluded that the TGF-beta-dependent decrease of 17alpha-hydroxylase/17,20 lyase activity in the H295R cells is caused by inhibition of CYP17 transcription and is mediated by the ALK5 receptor. ..
  47. Ivanov K, Puustinen P, Gabrenaite R, Vihinen H, Ronnstrand L, Valmu L, et al. Phosphorylation of the potyvirus capsid protein by protein kinase CK2 and its relevance for virus infection. Plant Cell. 2003;15:2124-39 pubmed
    ..These results suggest that the phosphorylation of PVA CP by CK2 plays an important regulatory role in virus infection. ..
  48. Franchi Gazzola R, Gaccioli F, Bevilacqua E, Visigalli R, Dall Asta V, Sala R, et al. The synthesis of SNAT2 transporters is required for the hypertonic stimulation of system A transport activity. Biochim Biophys Acta. 2004;1667:157-66 pubmed
    ..It is concluded that the synthesis of new SNAT2 transporters is essential for the hypertonic stimulation of transport system A, but accounts only in part for the adaptive increase of the system. ..
  49. Herrmann C, Rice A. Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J Virol. 1995;69:1612-20 pubmed
    ..Taken together, these results imply that TAK is a very promising candidate for a cellular factor that mediates Tat transactivation. ..
  50. Li L, Hu S, Wang S, Lee H, Wang Y, Ping Y. Positive transcription elongation factor b (P-TEFb) contributes to dengue virus-stimulated induction of interleukin-8 (IL-8). Cell Microbiol. 2010;12:1589-603 pubmed publisher
    ..This is the first demonstration of P-TEFb being directly involved in virus-induced host gene expression by interacting with a viral structural protein. ..
  51. Bhattacharya A, Lakka S, Mohanam S, Boyd D, Rao J. Regulation of the urokinase-type plasminogen activator receptor gene in different grades of human glioma cell lines. Clin Cancer Res. 2001;7:267-76 pubmed
    ..We conclude from our findings that increased transcription is the more likely mechanism underlying the increase in uPAR production in high-grade gliomas. ..
  52. Kawauchi J, Inoue M, Fukuda M, Uchida Y, Yasukawa T, Conaway R, et al. Transcriptional properties of mammalian elongin A and its role in stress response. J Biol Chem. 2013;288:24302-15 pubmed publisher
    ..Taken together, our data provide new insights into the function of Elongin A in RNAPII transcription and bring to light a previously unrecognized role for Elongin A in the regulation of stress response genes. ..
  53. Smillie D, Llinas A, Ryan J, Kemp G, Sommerville J. Nuclear import and activity of histone deacetylase in Xenopus oocytes is regulated by phosphorylation. J Cell Sci. 2004;117:1857-66 pubmed
    ..Thus, both translocation and activity of HDACm appear to be regulated by specific phosphorylation events. These results have implications for techniques involving the transfer of somatic nuclei into enucleated oocytes. ..