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Ghavidel, Ataollah; Hockman, Darren; Schultz, Michael

doi:10.1023/a:1006885522221

Cited by 16 publications

(4 citation statements)

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“…In theory, this property would ensure that SNAP C engages at appropriate snRNA promoter sites in the genome only in partnership with other components of the RNA polymerase III general machinery (19). This latter scenario is also consistent with CK2 function as a positive regulator of RNA polymerase III transcription in some contexts (20,32,33) and of cellular growth (34 -37), suggesting that CK2 might target SNAP190 to increase snRNA gene transcription during active cellular proliferation. However, the current data indicate that SNAP C phosphorylation is nonetheless inhibitory for U6 transcription.…”

Section: Discussionmentioning

confidence: 55%

The Protein Kinase CK2 Phosphorylates SNAP190 to Negatively Regulate SNAPC DNA Binding and Human U6 Transcription by RNA Polymerase III

Husain-Ponnampalam

Hoffmann-Benning

et al. 2007

Journal of Biological Chemistry

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In humans, polymerase specificity for snRNA 2 gene transcription depends upon the architecture of the core promoter region. snRNA genes containing solely a proximal sequence element (PSE) are transcribed by RNA polymerase II, whereas those containing juxtaposed PSE and TATA box elements are transcribed by RNA polymerase III (1). The human small nuclear RNA-activating protein complex (SNAP C ) is a general transcription factor that coordinates human snRNA gene transcription for both polymerases (2) through its ability to bind to the PSE (3), while serving as a target for numerous regulatory factors that influence snRNA gene transcription. SNAP C , also known as PTF (4), consists of five subunits called SNAP190 (PTF␣), SNAP50 (PTF␤), SNAP45 (PTF␦), SNAP43 (PTF␥), and SNAP19 (2, 5-10). Within this complex, PSE-specific binding is mediated by two of these factors SNAP190, which contains a Myb DNA binding domain (5), and SNAP50, which contains an unorthodox, but evolutionarily conserved zinc finger DNA binding domain (11). Neither SNAP190 nor SNAP50 can bind DNA alone, but instead are coordinated by SNAP43, which interacts with both factors to facilitate formation of a complex that is capable of DNA binding (12,13).In addition to its role in PSE recognition, SNAP190 plays a pivotal role in snRNA gene transcription by interacting with the TATA-box-binding protein (TBP), stimulating TBP promoter recruitment to TATA-box containing snRNA genes (14). Two regions within SNAP190 have been defined as playing a role in TBP recruitment. One TBP recruitment region (TRR1) is located toward the N terminus (15) and is adjacent to the region involved in SNAP C assembly with SNAP19 and SNAP43 (16). A second TBP recruitment region (TRR2) is located within the Myb DNA binding domain and was proposed to interact with the TBP DNA binding domain (13); these interactions are likely stabilized by adjacent binding of both factors at the PSE and TATA box, respectively. SNAP190 is also a direct target of the transcriptional activator protein Oct-1 (17, 18), which binds to an octamer sequence in the distal sequence element of human snRNA genes.As a central player in snRNA gene transcription, SNAP190 is also targeted for regulation through post-translational modification. For example, SNAP190 is phosphorylated both in vivo and in vitro, and in part, phosphorylation is mediated by the protein kinase CK2 that associates with and phosphorylates the N-terminal half of SNAP190 predominately at serine residues (19). CK2 associates with other components of the RNA polymerase III transcriptional machinery, including the Brf1-TFIIIB complex (20), as well as with RNA polymerase III itself (21). The functional consequences of CK2 association with these components of the RNA polymerase III transcriptional machinery are complex. CK2 phosphorylation of RNA polymerase III stimulates U6 snRNA gene transcription (21); however, during mitosis CK2 can instead down-regulate U6 transcription by phosphorylating Bdp1 (22), a component shared by both Brf1-TFIIIB and B...

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Section: Discussionmentioning

confidence: 55%

The Protein Kinase CK2 Phosphorylates SNAP190 to Negatively Regulate SNAPC DNA Binding and Human U6 Transcription by RNA Polymerase III

Husain-Ponnampalam

Hoffmann-Benning

et al. 2007

Journal of Biological Chemistry

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“…Again, SS2 phosphorylation decreased in both the S63A and S65A mutations, and was completely abolished by mutations that changed or removed both serine residues (S63/65A, TRU1, or TRU5). Heparin is an inhibitor of CKII in mammalian systems (Palmiter, 1973 ; Ghavidel et al, 1999 ). SS2 phosphorylation by recombinant CKII decreased with increasing heparin concentration, and was almost completely abolished by 1.0 mg/ml heparin.…”

Section: Resultsmentioning

confidence: 99%

Bioinformatic and in vitro Analyses of Arabidopsis Starch Synthase 2 Reveal Post-translational Regulatory Mechanisms

2018

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Starch synthase 2 (SS2) is an important enzyme in leaf starch synthesis, elongating intermediate-length glucan chains. Loss of SS2 results in a distorted starch granule phenotype and altered physiochemical properties, highlighting its importance in starch biosynthesis, however, the post-translational regulation of SS2 is poorly understood. In this study, a combination of bioinformatic and in vitro analysis of recombinant SS2 was used to identify and characterize SS2 post-translational regulatory mechanisms. The SS2 N-terminal region, comprising the first 185 amino acids of the mature protein sequence, was shown to be highly variable between species, and was predicted to be intrinsically disordered. Intrinsic disorder in proteins is often correlated with protein phosphorylation and protein-protein interactions. Recombinant Arabidopsis thaliana SS2 formed homodimers that required the N-terminal region, but N-terminal peptides could not form stable homodimers alone. Recombinant SS2 was shown to be phosphorylated by chloroplast protein kinases and recombinant casein kinase II at two N-terminal serine residues (S63, S65), but mutation of these phosphorylation sites (Ser>Ala) revealed that they are not required for homo-dimerization. Heteromeric enzyme complex (HEC) formation between SS2 and SBE2.2 was shown to be ATP-dependent. However, SS2 homo-dimerization and protein phosphorylation are not required for its interaction with SBE2.2, as truncation of the SS2 N-terminus did not disrupt ATP-dependent HEC assembly. SS2 phosphorylation had no affect on its catalytic activity. Intriguingly, the removal of the N-terminal region of SS2 resulted in a 47-fold increase in its activity. As N-terminal truncation disrupted dimerization, this suggests that SS2 is more active when monomeric, and that transitions between oligomeric state may be a mechanism for SS2 regulation.

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“…Most of the over 300 CK2 substrates have been found to be transcriptional factors (60), effectors of DNA/RNA structure (50) or signalling proteins (more than 80), and a limited number are metabolic enzymes [1]. As such, CK2 plays a critical role on multiple cellular processes, including cell survival [2], apoptosis [3], RNA synthesis [4] and cell transformation [5]. Moreover, CK2 is used by over 40 viruses [1] to phosphorylate the proteins that are essential to their life cycle, including Human Immunodeficiency Virus [6,7], Hepatitis B and C Viruses [8,9], and Human Cytomegalovirus [10].…”

Section: Introductionmentioning

confidence: 99%

Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

Liu

Hsieh

Yang

et al. 2013

BMC Pharmacol Toxicol

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BackgroundCasein kinase 2 (CK2) is involved in various cellular events such as proliferation, apoptosis, and the cell cycle. CK2 overexpression is associated with multiple human cancers and may therefore be a promising target for cancer therapy. To identity novel classes of inhibitors for CK2, we screened a natural product library obtained from National Cancer Institute.MethodsThe quantitative luminescent kinase assay ADP-Glo™ was used to screen CK2 inhibitors from the natural product library. The same assay was used to determine cell-free dose-dependent response of CK2 inhibitors and conduct a kinetic study. Docking was performed to predict the binding patterns of selected CK2 inhibitors. Western blot analysis was used to evaluate Akt phosphorylation specific to CK2 and apoptosis effect. The cell viability assay CellTiter-Glo® was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells.ResultsWe identified coumestrol as a novel reversible ATP competitive CK2 inhibitor with an IC50 value of 228 nM. Coumestrol is a plant-derived compound that belongs to the class of phytoestrogens, natural compounds that mimic the biological activity of estrogens. In our study, coumestrol showed high selectivity among 13 kinases. The hydrogen bonds formed between coumestrol and the amino acids in the ATP binding site were first reviewed by a molecular docking study that suggested a possible interaction of coumestrol with the hinge region of ATP site of CK2. In addition, coumestrol inhibited cancer cell growth partially through down-regulation of CK2-specific Akt phosphorylation. Finally, coumestrol exerted strong inhibition effects on the growth of three cancer cell lines.ConclusionOur study shows that coumestrol, a novel ATP competitive and cell permeable CK2 inhibitor with submicromolar IC50, had inhibition effects on the growth of three cancer cell lines and may represent a promising class of CK2 inhibitors.

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Cited by 16 publications

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The Protein Kinase CK2 Phosphorylates SNAP190 to Negatively Regulate SNAPC DNA Binding and Human U6 Transcription by RNA Polymerase III

The Protein Kinase CK2 Phosphorylates SNAP190 to Negatively Regulate SNAPC DNA Binding and Human U6 Transcription by RNA Polymerase III

Bioinformatic and in vitro Analyses of Arabidopsis Starch Synthase 2 Reveal Post-translational Regulatory Mechanisms

Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

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