Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endoplasmic reticulum (ER) has a characteristic complex polygonal structure with hallmark three-way junctions in many types of cells. To investigate the mechanisms responsible for maintaining the ER network, we established ER disassembly and reassembly assays in semi-intact Chinese hamster ovary (CHO) cells that constitutively expressed heat shock protein-47 fused to the green fluorescent protein (GFP-HSP47) as an ER marker (the cells are referred to as CHO-HSP cells). Using these assays, we found that maintenance of the ER network required cytosol and adenosine triphosphate/guanosine 5'-triphosphate (ATP/GTP) hydrolysis, but not actin filaments or microtubules. We also showed that the ER network was disrupted upon addition of either N-ethylmaleimide-treated cytosol after washing semi-intact cells with high salt solution or mitotic cytosol in nocodazole-treated semi-intact CHO-HSP cells. The disrupted ER network induced by mitotic cytosol was reformed by the addition of interphase cytosol. In addition, we found that p47, a cofactor of p97, was essential for the maintenance of the ER network, and that phosphorylation of p47 by cdc2 kinase resulted in ER network disruption by mitotic cytosol. Taken together, these results imply that the maintenance of the ER network requires a membrane fusion process mediated by p97/p47, and that cell cycle-dependent morphological changes of the ER network are regulated through phosphorylation/dephosphorylation of p47.
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PMID:The maintenance of the endoplasmic reticulum network is regulated by p47, a cofactor of p97, through phosphorylation by cdc2 kinase. 1577 96

Predicting off-targets by computational methods is getting increasing importance in early drug discovery stages. We herewith present a computational method based on binding site three-dimensional comparisons, which prompted us to investigate the cross-reaction of protein kinase inhibitors with synapsin I, an ATP-binding protein regulating neurotransmitter release in the synapse. Systematic pair-wise comparison of the staurosporine-binding site of the proto-oncogene Pim-1 kinase with 6,412 druggable protein-ligand binding sites suggested that the ATP-binding site of synapsin I may recognize the pan-kinase inhibitor staurosporine. Biochemical validation of this hypothesis was realized by competition experiments of staurosporine with ATP-gamma(35)S for binding to synapsin I. Staurosporine, as well as three other inhibitors of protein kinases (cdk2, Pim-1 and casein kinase type 2), effectively bound to synapsin I with nanomolar affinities and promoted synapsin-induced F-actin bundling. The selective Pim-1 kinase inhibitor quercetagetin was shown to be the most potent synapsin I binder (IC50 = 0.15 microM), in agreement with the predicted binding site similarities between synapsin I and various protein kinases. Other protein kinase inhibitors (protein kinase A and chk1 inhibitor), kinase inhibitors (diacylglycerolkinase inhibitor) and various other ATP-competitors (DNA topoisomerase II and HSP-90alpha inhibitors) did not bind to synapsin I, as predicted from a lower similarity of their respective ATP-binding sites to that of synapsin I. The present data suggest that the observed downregulation of neurotransmitter release by some but not all protein kinase inhibitors may also be contributed by a direct binding to synapsin I and phosphorylation-independent perturbation of synapsin I function. More generally, the data also demonstrate that cross-reactivity with various targets may be detected by systematic pair-wise similarity measurement of ligand-annotated binding sites.
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PMID:Binding of protein kinase inhibitors to synapsin I inferred from pair-wise binding site similarity measurements. 2080 48

Chronic liver disease is an important cause of morbidity and mortality in the United States. Despite significant advances, the treatment options for many chronic liver diseases are limited. Recently, oligonucleotide-based therapeutics emerged as a novel treatment approach for a number of liver diseases. Therapeutic oligonucleotides comprised of 15 to 30 nucleotides in length that work in complementary to a specific region of a messenger RNA (mRNA) encoding a disease-related protein or a regulatory non-coding RNA and interfere with the target gene expression. These oligonucleotides can bind with high affinity and specificity through RNA-RNA or RNA-DNA base-pairing and targets the expression of mRNA leading to the disease control. A large number of druggable targets including miR-122, miR-132, miR-34, HSP 47, PNPLA3, STK25 etc., have emerged as susceptible molecular targets in the liver to treat various diseases. Thus, chronic liver diseases may be treated effectively by modulating these susceptible molecular targets using novel therapeutic oligonucleotides. Currently, several preclinical and clinical studies are underway to evaluate the clinical effectiveness and safety of different oligonucleotide therapies in the treatment of chronic liver diseases. In order to optimize its clinical effectiveness, various strategies have been explored including chemical modifications of the oligonucleotides and developing effective drug delivery systems such as oligonucleotide -ligand conjugates, oligonucleotide-polymer conjugates, and lipid or polymer-based nano-carriers. In this review, we provide an overview of the historical perspectives, the mechanism of action, delivery technologies, and clinical experience of using oligonucleotide-based therapies in treating liver diseases.
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PMID:Oligonucleotide-Based Therapeutics: An Emerging Strategy for the Treatment of Chronic Liver Diseases. 3297 89