calyculin-a and nodularin
calyculin-a has been researched along with nodularin* in 9 studies
Reviews
2 review(s) available for calyculin-a and nodularin
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Cell Death Inducing Microbial Protein Phosphatase Inhibitors--Mechanisms of Action.
Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca(2+)/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity. Topics: Animals; Apoptosis; Carcinogens; Cell Death; Enzyme Inhibitors; Humans; Marine Toxins; Microcystins; Okadaic Acid; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Reactive Oxygen Species | 2015 |
Specific mechanistic aspects of animal tumor promoters: the okadaic acid pathway.
Topics: Animals; Antifungal Agents; Carcinogens; Ethers, Cyclic; Liver Neoplasms; Marine Toxins; Mice; Molecular Structure; Okadaic Acid; Oxazoles; Peptides, Cyclic; Pyrans; Rats; Skin Neoplasms; Spiro Compounds; Stomach Neoplasms; Structure-Activity Relationship | 1992 |
Other Studies
7 other study(ies) available for calyculin-a and nodularin
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Small-molecule inhibitors of ser/thr protein phosphatases: specificity, use and common forms of abuse.
Natural product extracts have proven to be a rich source of small molecules that potently inhibit the catalytic activity of certain PPP-family ser/thr protein phosphatases. To date, the list of inhibitors includes okadaic acid (produced by marine dinoflagelates, Prorocentrum sp. and Dinophysis sp.), calyculin A, dragmacidins (isolated from marine sponges), microcystins, nodularins (cyanobacteria, Microcystis sp. and Nodularia sp.), tautomycin, tautomycetin, cytostatins, phospholine, leustroducsins, phoslactomycins, fostriecin (soil bacteria, Streptomyces sp.), and cantharidin (blister beetles, approx 1500 species). Many of these compounds share structural similarities, and several have become readily available for research purposes. Here we will review the specificity of available inhibitors and present methods for their use in studying sensitive phosphatases. Common mistakes in the employment of these compounds will also be addressed briefly, notably the widespread misconception that they only inhibit the activity of PP1 and PP2A. Inhibitors of PP2B (calcineurin) will only be mentioned in passing, except to state that, in our hands, cypermethrin, deltamethrin, and fenvalerate, which are sold as potent inhibitors of PP2B, do not inhibit the catalytic activity of PP2B. Topics: Cantharidin; Enzyme Inhibitors; Furans; Indole Alkaloids; Lactones; Lipids; Marine Toxins; Microcystins; Okadaic Acid; Organophosphates; Organophosphorus Compounds; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Pyrans; Pyrones; Spiro Compounds | 2007 |
Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors.
The protein phosphatase (PP) inhibitors nodularin and microcystin-LR induced apoptosis with unprecedented rapidity, more than 50% of primary hepatocytes showing extensive surface budding and shrinkage of cytoplasm and nucleoplasm within 2 min. The apoptosis was retarded by the general caspase inhibitor Z-VAD.fmk. To circumvent the inefficient uptake of microcystin and nodularin into nonhepatocytes, toxins were microinjected into 293 cells, Swiss 3T3 fibroblasts, promyelocytic IPC-81 cells, and NRK cells. All cells started to undergo budding typical of apoptosis within 0.5 - 3 min after injection. This was accompanied by cytoplasmic and nuclear shrinkage and externalization of phosphatidylserine. Overexpression of Bcl-2 did not delay apoptosis. Apoptosis induction was slower and Z-VAD.fmk independent in caspase-3 deficient MCF-7 cells. MCF-7 cells stably transfected with caspase-3 showed a more rapid and Z-VAD.fmk dependent apoptotic response to nodularin. Rapid apoptosis induction required inhibition of both PP1 and PP2A, and the apoptosis was preceded by increased phosphorylation of several proteins, including myosin light chain. The protein phosphorylation occurred even in the presence of apoptosis-blocking concentrations of Z-VAD.fmk, indicating that it occurred upstream of caspase activation. It is suggested that phosphatase-inhibiting toxins can induce caspase-3 dependent apoptosis in an ultrarapid manner by altering protein phosphorylation. Topics: 3T3 Cells; Animals; Antifungal Agents; Apoptosis; Caspase 3; Caspase Inhibitors; Caspases; Cell Line; Cell Line, Transformed; Enzyme Inhibitors; Gene Expression; Humans; Intracellular Fluid; Marine Toxins; Mice; Microcystins; Okadaic Acid; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Pyrans; Rats; Rats, Wistar; Spiro Compounds; Tumor Cells, Cultured | 1999 |
Sensitive detection of apoptogenic toxins in suspension cultures of rat and salmon hepatocytes.
A number of algal toxins were tested for the ability to induce apoptosis (regulated cell death) in primary hepatocytes from salmon and rat. The tested toxins included the liver targeting substances microcystin-LR and nodularin, substances associated with the diarrhetic shellfish poison complex (okadaic acid, dinophysistoxin-1 and pectenotoxin-1) and calyculin A. All toxins induced apoptosis in both salmon and rat hepatocytes in less than 2 h. The apoptotic changes were evident both by electron and light microscopy and were counteracted by the caspase inhibitor ZVAD-fmk and by the Ca2+/calmodulin dependent kinase II inhibitor KN-93. The salmon hepatocytes were 10-20-fold more sensitive to okadaic acid and dinophysistoxin-1 (EC50=20 nM) than rat hepatocytes and other mammalian cell lines tested. An assay was devised using hepatocyte apoptosis as parameter for detection of algal toxins. This assay was at least as sensitive as HPLC determination for okadaic acid in mussel extracts. It also detected algal toxins which do not inhibit protein phosphatases, like pectenotoxin-1. Subapoptotic concentrations of the toxins inhibited hepatocyte aggregation. Using this parameter, less than 200 pg okadaic acid could be detected. In conclusion, salmon hepatocytes in suspension culture provide a rapid and sensitive system for detection of a broad range of apoptogenic toxins. Topics: Animals; Apoptosis; Cell Aggregation; Cells, Cultured; Eukaryota; Liver; Marine Toxins; Microcystins; Okadaic Acid; Oxazoles; Peptides, Cyclic; Pyrans; Rats | 1998 |
A model for binding of structurally diverse natural product inhibitors of protein phosphatases PP1 and PP2A.
Protein phosphatases play significant roles in signal transduction pathways pertaining to cell proliferation, gene expression, and neurotransmission. Serine/threonine phosphatases PP1 and PP2A, which are closely related in primary structure (approximately 50%), are inhibited by a structurally diverse group of natural toxins. As part of our study toward understanding the mechanism of inhibition displayed by these toxins, we have developed research in two directions: (1) The standardization of an assay to be used in acquisition of the structure--activity relationship of inhibition data is reported. This nonradioactive assay affords detection levels of molecular phosphate released from a phosphorylated hexapeptide in subnanomolar quantities. The comparison of our IC50 values of these inhibitors against corresponding literature data provided validation for our method. (2) Computational analysis provided a global model for binding of these inhibitors to PP1. The natural toxins were shown to possess remarkably similar three-dimensional motifs upon superimposition and van der Waals minimization within the PP1 active site. Topics: Antifungal Agents; Crystallography, X-Ray; Enzyme Inhibitors; Marine Toxins; Microcystins; Models, Molecular; Okadaic Acid; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Protein Binding; Protein Conformation; Pyrans; Signal Transduction; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship; Toxins, Biological | 1997 |
A mutant of protein phosphatase-1 that exhibits altered toxin sensitivity.
A chimeric mutant was constructed in which a 4-amino acid region (GEFD, residues 274-277) of rabbit muscle protein phosphatase-1 was replaced with the sequence YRCG corresponding to residues 267-270 of rabbit protein phosphatase-2A. This was based on the findings of a gene mutation in okadaic acid-resistant cells which results in a Cys-->Gly conversion in protein phosphatase-2A. The YRCG mutant of protein phosphatase-1 was expressed and purified. The properties of the mutant enzyme were investigated in terms of its sensitivity toward several toxin inhibitors (okadaic acid, microcystin, nodularin, calyculin A, and cantharidic acid), as well as inhibitor-2. The mutant enzyme exhibited a gain of function in the form of a 10-fold increased sensitivity toward okadaic acid that suggests this region is involved in toxin binding. Significant changes in sensitivity to inhibitor-2 and several of the other toxins were also observed, indicating that these may have a common binding region. Topics: Amino Acid Sequence; Animals; DNA Primers; Ethers, Cyclic; Kinetics; Marine Toxins; Microcystins; Molecular Sequence Data; Mutagenesis, Site-Directed; Okadaic Acid; Oxazoles; Peptides, Cyclic; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Phosphatase 2; Rabbits; Recombinant Fusion Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship | 1994 |
Characterization of natural toxins with inhibitory activity against serine/threonine protein phosphatases.
Recent studies suggest that the ability to inhibit the activity of certain serine/threonine protein phosphatases underlies the toxicity of several natural compounds including: okadaic acid, microcystin-LR, nodularin, calyculin A and tautomycin. To characterize further the actions of these toxins, this study compares the inhibitory effects of okadaic acid, chemical derivatives of okadaic acid, microcystin-LR, microcystin-LA, nodularin, calyculin A and tautomycin on the activity of serine/threonine protein phosphatases types 1 (PP1), 2A (PP2A) and a recently identified protein phosphatase purified from bovine brain (PP3). This study shows that, like PP1 and PP2A, the activity of PP3 is potently inhibited by okadaic acid, both microcystins, nodularin, calyculin A and tautomycin. Further characterization of the toxins employing the purified catalytic subunits of PP1, PP2A and PP3 under identical experimental conditions indicates that: (a) okadaic acid, microcystin-LR, and microcystin-LA inhibit PP2A and PP3 more potently than PP1 (order of potency PP2A > PP3 > PP1); (b) nodularin inhibits PP1 and PP3 at a similar concentration that is slightly higher than that which affects PP2A, and (c) both calyculin A and tautomycin show little selectivity among the phosphatases tested. This study also shows that the chemical modification of the (C1) carboxyl group of okadaic acid can have a profound influence on the inhibitory activity of this toxin. Esterification of okadaic acid, producing methyl okadaate, or reduction, producing okadaol, greatly decreases the inhibitory effects against all three enzymes tested. Further reduction, producing 1-nor-okadaone, or acetylation, producing okadaic acid tetraacetate, results in compounds with no inhibitory activity. In contrast, the substitution of alanine (-LA) for arginine (-LR) in microcystin has no apparent effect on the inhibitory activity against PP1, PP2A or PP3. Topics: Animals; Antifungal Agents; Cattle; Cyclic AMP-Dependent Protein Kinases; Esterification; Ethers, Cyclic; Marine Toxins; Microcystins; Okadaic Acid; Oxazoles; Oxidation-Reduction; Peptides, Cyclic; Phosphoprotein Phosphatases; Phosphorylase b; Phosphorylase Kinase; Pyrans; Rabbits; Spiro Compounds | 1994 |
Characterization of serine/threonine protein phosphatases in RINm5F insulinoma cells.
This study investigates the occurrence and regulation of serine/threonine protein phosphatases (PPases) in insulin-secreting RINm5F insulinoma cells. PPases types 1 and 2A were identified in crude RINm5F cell homogenates by both enzymatic assay and Western blot analysis. We then characterized and compared the inhibitory actions of several compounds isolated from cyanobacteria, marine dinoflagellates and marine sponges, (viz. okadaic acid, microcystin-LR, calyculin-A and nodularin) cation-independent PPase activities in RINm5F cell homogenates. It was found that okadaic acid was the least potent inhibitor (IC50 approximately 10(-9) M, IC100 approximately 10(-6) M), while the other compounds exhibited IC50 values of approximately 5 x 10(-10) M and IC100 approximately 5 x 10(-9) M. The findings indicate that the inhibitory substances employed in this study may be used pharmacologically to investigate the role of serine/threonine PPases in RINm5F cell insulin secretion, a process that is likely to be regulated to a major extent by protein phosphorylation. Topics: Animals; Ethers, Cyclic; In Vitro Techniques; Insulinoma; Marine Toxins; Microcystins; Okadaic Acid; Oxazoles; Pancreatic Neoplasms; Peptides, Cyclic; Phosphoprotein Phosphatases; Rabbits; Rats; Tumor Cells, Cultured | 1993 |