The Replacement of ATP by the Competitive Inhibitor Emodin Induces Conformational Modifications in the Catalytic Site of Protein Kinase CK2

Battistutta, Roberto; Sarno, Stefania; Moliner, E. De; Papinutto, E.; Zanotti, Giuseppe; Pinna, Lorenzo A.

doi:10.1074/jbc.m004257200

Cited by 145 publications

(125 citation statements)

References 29 publications

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“…1A). Administration of emodin (20 mg/kg/d), a CK2 inhibitor, 18) in the anti-GBM antibody-injected rats ameliorated the development of proteinuria significantly (Fig. 1A), which is in agreement with our previous study.…”

Section: Effects Of Administration Of the Tricaprylin Emulsion Or Emosupporting

confidence: 82%

Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: In Vivo and in Silico Studies

Liu

Shi

Xiao

et al. 2015

Biological & Pharmaceutical Bulletin

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Glomerulonephritis (GN) is a set of pathological conditions that result in the destruction of glomeruli and loss of renal function, commonly leading to the development of end-stage renal disease. Current pharmacotherapy is limited to immunosuppressive therapy. In the present study, we found a novel antinephritic effect of a tricaprylin emulsion in the anti-glomerular basement membrane (anti-GBM) GN rat model. We evaluated the treatment in vivo by comparing administration of the emulsion with administration of a casein kinase II (CK2) inhibitor in this rat model, and performed a gene ontology-based microarray analysis to reveal in silico the detailed mechanism of action. Our results showed that administration of the tricaprylin emulsion, or even tricaprylin alone, significantly ameliorated the anti-GBM antibody-induced renal dysfunction in these rats. We believe that tricaprylin is the key active antinephritic component of the emulsion and might be a promising drug for the effective treatment of nephritis. Moreover, with respect to microarray analysis, we developed a generally applicable and rapid method to compare gene expression profile data for multiple models of nephritis and clinical samples from a public domain microarray database.Key words tricaprylin; crescentic glomerulonephritis; microarray; gene ontology Glomerulonephritis (GN) is a progressive inflammation of the glomeruli that can be caused by a variety of underlying disorders. It is one of the primary causes of renal failure and end-stage renal disease that require dialysis and transplantation. Immunosuppressive therapy has been used to treat GN clinically, but the therapeutic benefits of this treatment are limited and the treatment per se can also cause renal damage. 1)Crescentic GN is also called rapidly progressive GN; if left untreated, it rapidly progresses into acute renal failure. Anti-glomerular basement membrane (anti-GBM) GN is a typical type of crescentic GN. It is characterized clinically by the rapid deterioration of renal function and histologically by mononuclear cell infiltration into the stroma, glomerular cell proliferation, crescent formation in the glomerulus with the deposition of anti-GBM antibodies.2) To investigate this disease, we utilized an experimental model in Wistar-Kyoto (WKY) rats, in which injection of rabbit anti-rat GBM antiserum induces severe proliferative and necrotizing GN with crescent formation that resembles human anti-GBM GN. 3)Previously, we identified the protein kinase casein kinase II (CK2) as a GN-related gene through microarray analysis performed on these anti-GBM GN model rats, and demonstrated that in vivo inhibition of the kinase ameliorates renal dysfunction and histological progression of the condition.2) Furthermore, previous studies using the same model of anti-GBM GN have suggested that several genes are also relevant to the onset of anti-GBM GN. 4)The study reported herein shows a novel antinephritic effect observed in the anti-GBM GN rat model following administration of an emulsion containi...

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Section: Effects Of Administration Of the Tricaprylin Emulsion Or Emosupporting

confidence: 82%

Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: In Vivo and in Silico Studies

Liu

Shi

Xiao

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Emodin exerts its pleiotropic anti-cancer effects through diverse mechanisms including the activation of caspase-3 [23] and upregulation of p53 and p21 [26]. Moreover, emodin has been reported to inhibit the kinase activity/activation of p56lck, HER2/neu [21], casein kinase [27], NF-jB [28], activator protein 1 [29,30], AKT [30], matrix metalloproteinases [29,31], and the expression of chemokine receptor CXCR4 [32]. Our findings specifically in HCC cells clearly indicate that this quinone can enhance TRAIL-induced apoptosis through the downregulation of antiapoptotic proteins, upregulation of death receptors and the activation of C/EBP homologous protein (CHOP).…”

Section: Introductionmentioning

confidence: 99%

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

et al. 2013

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Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently under clinical trials for cancer, however many tumor cells, including hepatocellular carcinoma (HCC) develop resistance to TRAIL-induced apoptosis. Hence, novel agents that can alleviate TRAIL-induced resistance are urgently needed. In the present report, we investigated the potential of emodin to enhance apoptosis induced by TRAIL in HCC cells. As observed by MTT cytotoxicity assay and the externalization of the membrane phospholipid phosphatidylserine, we found that emodin can significantly potentiate TRAIL-induced apoptosis in HCC cells. When investigated for the mechanism(s), we observed that emodin can downregulate the expression of various cell survival proteins, and induce the cell surface expression of both TRAIL receptors, death receptors (DR) 4 as well as 5. In addition, emodin increased the expression of C/EBP homologous protein (CHOP) in a time-dependent manner. Knockdown of CHOP by siRNA decreased the induction of emodin-induced DR5 expression and apoptosis. Emodin-induced induction of DR5 was mediated through the generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of DR5 and the induction of apoptosis. Also, the knockdown of X-linked inhibitor of apoptosis protein by siRNA significantly reduced the sensitization effect of emodin on TRAILinduced apoptosis. Overall, our experimental results clearly indicate that emodin can indeed potentiate TRAIL-induced Aruljothi Subramaniam and Ser Yue Loo contributed equally to this work.

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“…CK2 can be inhibited by the glycosaminoglycan heparin and by dichlororibofuranosylbenzimidazole (DRB); these drugs are relatively non-specific, the former being a polyanion that interacts with many enzymes on the basis of charge and the latter being a general inhibitor of transcription when used on intact cells. Thus, we employed two more selective inhibitors of CK2: apigenin (also known as chrysin), a flavonoid antioxidant (Critchfield et al, 1996(Critchfield et al, , 1997; and emodin, an anthraquinone (Battistutta et al, 2000;Yim et al, 1999). Though not completely specific (Agullo et al, 1997;Lin et al, 1997;Reddy et al, 1999;Yin et al, 1999), CK2 is one of the few targets they are known to share, and thus phosphorylation reactions in which GTP can be employed that are blocked by these two chemically unrelated inhibitors are likely to be mediated by CK2.…”

Section: Ck2 Phosphorylates a C-myc-gst Fusion Protein In Vitromentioning

confidence: 99%

Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis

2002

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Protein kinase CK2 (formerly casein kinase II) is frequently upregulated in human cancers, and transgenic expression of CK2a in lymphocytes is oncogenic. Lymphomagenesis is dramatically acclerated by coexpression of a c-myc transgene, suggestive of a synergistic interaction between the kinase and the transcription factor. Since c-myc can be phosphorylated by CK2, we hypothesized that the synergy between CK2 and c-myc might be due to a functional interaction of the two molecules. Pharmacologic inhibition of CK2 activity in cell lines established from CK2a transgenic T cell lymphomas reduces their proliferation and concomitantly with this, the steady state levels of c-myc protein decline. This is caused by acclerated c-myc protein turnover, which occurs in a proteasome-dependent manner. Transfection of cells with sense or anti-sense CK2 constructs modulates c-myc protein levels in concert with the alteration in CK2 activity, validating the findings obtained using the kinase inhibitors. Thus, CK2 is a critical regulator of c-myc protein stability and of the proliferation of these T cell lymphomas.

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The Replacement of ATP by the Competitive Inhibitor Emodin Induces Conformational Modifications in the Catalytic Site of Protein Kinase CK2

Cited by 145 publications

References 29 publications

Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: <i>In Vivo</i> and <i>in Silico</i> Studies

Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: <i>In Vivo</i> and <i>in Silico</i> Studies

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis

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