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Chemical Compound Review

AC1L7877     [(3R,9S)-2-[(3R,5S)-14-cyano- 3,5-dihydroxy...

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Disease relevance of NSC611747

  • Activation of the 63- and 40-kDa protein kinases was blocked by pertussis toxin, calyculin A, and staurosporine [1].
  • First, cell treatment with two phosphatase inhibitors, okadaic acid and calyculin A, prevented the hypophosphorylation of the retinoblastoma family proteins, at concentrations that specifically inhibit PP2A [2].
  • Phosphoseryl/threonyl protein phosphatase inhibitors, viz. okadaic acid and calyculin-A, failed to induce nuclear factor-kappa B (NF-kappa B) nuclear translocation in several primary human cells although a marked and rapid induction was observed in their simian virus 40 transformed counterparts [3].
  • At concentrations of 3.3 nM and greater, calyculin-A inhibited, in a dose-dependent manner, stimulated bone resorption [4].
  • Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity [5].

High impact information on NSC611747

  • Propranolol, an inhibitor of phosphatidate phosphohydrolase, and calyculin A, a phosphatase 1 and 2A inhibitor, blocked DAG production in response to FMLP but not to IL-4 [6].
  • Indeed, calyculin A, which inhibits protein phosphatases 1 and 2A, effectively blocked hyperosmotic stress-mediated inactivation (dephosphorylation) of PKBalpha [7].
  • In addition, the light-inducible expression of two photosynthetic fusion genes can be specifically suppressed by the structurally unrelated PP1 and PP2A inhibitors, okadaic acid and calyculin A, using a sensitive and physiological maize protoplast transient assay [8].
  • We show that calyculin A, which triggers chromosome condensation at any phase of the cell cycle but does not markedly impair replication, induces damage in the chromosomes of human lymphocytes treated in G(2) but not in G(1) phase [9].
  • We also show that, in cells that go through an unperturbed S phase, completion of their replication and/or replication-associated chromatin reorganization occur all along the G(2) phase, which may explain their inability to condense properly after calyculin A treatment during this phase of the cell cycle [9].

Chemical compound and disease context of NSC611747


Biological context of NSC611747


Anatomical context of NSC611747

  • To assess the possible functions of protein phosphatases in this respect, we studied the effects of the phosphatase inhibitors calyculin A, okadaic acid, and dinophysistoxin 1 (35-methylokadaic acid) on BHK-21 fibroblasts [18].
  • These results show that the protein phosphatase inhibitor calyculin A leads to rapid hyperphosphorylation of specific proteins in cultured cells and indicate that elicitor action could be based on inhibition of a protein phosphatase as well as on activation of a protein kinase [13].
  • Furthermore, the induced phosphatase activity coimmunoprecipitated with the hyperphosphorylated RB and was active in a cell-free system that reproduced the growth arrest- and apoptosis-specific RB dephosphorylation, which was inhibitable by calyculin A but not zinc [19].
  • The phosphatase inhibitors okadaic acid and calyculin A were found to elicit or to modify several neutrophil responses, suggesting that dephosphorylation plays a regulatory role [16].
  • Mutation of the PP1-binding motif or PP1 inhibition by okadaic acid and calyculin A abolished filopodia and restored stress fibers in cells expressing neurabin I [20].

Associations of NSC611747 with other chemical compounds

  • Phosphorylation of CPI-17 in rabbit arteries was enhanced by calyculin A but not okadaic acid or fostriecin, consistent with PP1-mediated dephosphorylation [21].
  • Inhibition of protein phosphatase 1 (PP1) and/or protein phosphatase 2A (PP2A) by the specific inhibitor calyculin A occluded the PKA-mediated potentiation of striatal NMDA responses, suggesting that the PKA effect was mediated by inhibition of a protein phosphatase [22].
  • GADD34 expression also reversed eIF-2 alpha phosphorylation induced by okadaic acid but not that induced by another phosphatase inhibitor, calyculin A (CA), which is a result consistent with PP1 being a component of the GADD34-assembled eIF-2 alpha phosphatase [23].
  • OAR1 and 2 were cross-resistant to other phosphatase inhibitors (calyculin A, cantharidin), but not to staurosporine or microinjected Cytochrome c, thus, indicating a disturbance in a limited number of death pathways, upstream or independent of apaf-1/caspases-3/9 [24].
  • Consistent with this, the reduction in serine 473 phosphorylation was inhibited by the phosphatase inhibitors okadaic acid and calyculin A [25].

Gene context of NSC611747

  • In addition, the dephosphorylation of PKB was prevented by pretreatment with the phosphatase inhibitors okadaic acid and calyculin A [26].
  • We additionally show the near complete restoration of NKCC1 activity in the presence of the protein phosphatase type 1 inhibitor calyculin A, demonstrating that DNPASK inhibition results from an alteration in kinase/phosphatase dynamics rather than from a decrease in functional cotransporter expression [27].
  • Immunofluorescence microscopy demonstrated localization of TRPC1, TRPC3, and TRPC4 to the PMN cell membrane and their internalization after cytoskeletal reorganization by calyculin A (CalyA) [28].
  • Neutrophil exposure to the Ser/Thr phosphatase inhibitors okadaic acid and calyculin A induced JNK activation [29].
  • We also show that treatment with calyculin A, a protein phosphatase inhibitor, leads to a marked increase of HDAC7 but not HDAC5 [30].

Analytical, diagnostic and therapeutic context of NSC611747


  1. Stimulation of neutrophils with a chemoattractant activates several novel protein kinases that can catalyze the phosphorylation of peptides derived from the 47-kDa protein component of the phagocyte oxidase and myristoylated alanine-rich C kinase substrate. Ding, J., Badwey, J.A. J. Biol. Chem. (1993) [Pubmed]
  2. Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. Cicchillitti, L., Fasanaro, P., Biglioli, P., Capogrossi, M.C., Martelli, F. J. Biol. Chem. (2003) [Pubmed]
  3. Differential induction of nuclear NF-kappa B by protein phosphatase inhibitors in primary and transformed human cells. Requirement for both oxidation and phosphorylation in nuclear translocation. Menon, S.D., Qin, S., Guy, G.R., Tan, Y.H. J. Biol. Chem. (1993) [Pubmed]
  4. Protein phosphatase inhibitors and bone resorption: inhibition by okadaic acid and biphasic actions of calyculin-A. Goad, D.L., Meurer, E.A., Voelkel, E.F., Petrou, C.P., Tashjian, A.H. Endocrinology (1992) [Pubmed]
  5. Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. Li, S.P., Deng, Y.Q., Wang, X.C., Wang, Y.P., Wang, J.Z. J. Pineal Res. (2004) [Pubmed]
  6. Interleukin 4 receptor signaling in human monocytes and U937 cells involves the activation of a phosphatidylcholine-specific phospholipase C: a comparison with chemotactic peptide, FMLP, phospholipase D, and sphingomyelinase. Ho, J.L., Zhu, B., He, S., Du, B., Rothman, R. J. Exp. Med. (1994) [Pubmed]
  7. Inactivation and dephosphorylation of protein kinase Balpha (PKBalpha) promoted by hyperosmotic stress. Meier, R., Thelen, M., Hemmings, B.A. EMBO J. (1998) [Pubmed]
  8. Protein phosphatase activity is required for light-inducible gene expression in maize. Sheen, J. EMBO J. (1993) [Pubmed]
  9. Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites. El Achkar, E., Gerbault-Seureau, M., Muleris, M., Dutrillaux, B., Debatisse, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Phosphorylation state of hsp27 and p38 MAPK during preconditioning and protein phosphatase inhibitor protection of rabbit cardiomyocytes. Armstrong, S.C., Delacey, M., Ganote, C.E. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  11. Differential modulation of pharmacologically distinct components of Ca2+ currents by protein kinase C activators and phosphatase inhibitors in nerve-growth-factor-differentiated rat pheochromocytoma (PC12) cells. Bouron, A., Reber, B.F. Pflugers Arch. (1994) [Pubmed]
  12. Modulation of CFTR chloride channels by calyculin A and genistein. Yang, I.C., Cheng, T.H., Wang, F., Price, E.M., Hwang, T.C. Am. J. Physiol. (1997) [Pubmed]
  13. The protein phosphatase inhibitor calyculin A mimics elicitor action in plant cells and induces rapid hyperphosphorylation of specific proteins as revealed by pulse labeling with [33P]phosphate. Felix, G., Regenass, M., Spanu, P., Boller, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  14. Calyculin A induces contractile ring-like apparatus formation and condensation of chromosomes in unfertilized sea urchin eggs. Tosuji, H., Mabuchi, I., Fusetani, N., Nakazawa, T. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  15. Role of phosphorylation in elicitation of the oxidative burst in cultured soybean cells. Chandra, S., Low, P.S. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  16. Protein phosphatase inhibitors okadaic acid and calyculin A alter cell shape and F-actin distribution and inhibit stimulus-dependent increases in cytoskeletal actin of human neutrophils. Kreienbühl, P., Keller, H., Niggli, V. Blood (1992) [Pubmed]
  17. Comparative cytotoxic effects of two protein phosphatase inhibitors, okadaic acid and calyculin A, on thyroid cells. Golstein, J., Swillens, S., Dumont, J.E. Cell Death Differ. (1995) [Pubmed]
  18. Cytoskeletal integrity in interphase cells requires protein phosphatase activity. Eriksson, J.E., Brautigan, D.L., Vallee, R., Olmsted, J., Fujiki, H., Goldman, R.D. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  19. Induction of a retinoblastoma phosphatase activity by anticancer drugs accompanies p53-independent G1 arrest and apoptosis. Dou, Q.P., An, B., Will, P.L. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  20. Targeting protein phosphatase 1 (PP1) to the actin cytoskeleton: the neurabin I/PP1 complex regulates cell morphology. Oliver, C.J., Terry-Lorenzo, R.T., Elliott, E., Bloomer, W.A., Li, S., Brautigan, D.L., Colbran, R.J., Shenolikar, S. Mol. Cell. Biol. (2002) [Pubmed]
  21. Phosphoprotein inhibitor CPI-17 specificity depends on allosteric regulation of protein phosphatase-1 by regulatory subunits. Eto, M., Kitazawa, T., Brautigan, D.L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  22. The phosphoprotein DARPP-32 mediates cAMP-dependent potentiation of striatal N-methyl-D-aspartate responses. Blank, T., Nijholt, I., Teichert, U., Kügler, H., Behrsing, H., Fienberg, A., Greengard, P., Spiess, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  23. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Brush, M.H., Weiser, D.C., Shenolikar, S. Mol. Cell. Biol. (2003) [Pubmed]
  24. Establishment of okadaic acid resistant cell clones using a cDNA expression library. Sandal, T., Ahlgren, R., Lillehaug, J., Døskeland, S.O. Cell Death Differ. (2001) [Pubmed]
  25. Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. Schubert, K.M., Scheid, M.P., Duronio, V. J. Biol. Chem. (2000) [Pubmed]
  26. Osmotic shock inhibits insulin signaling by maintaining Akt/protein kinase B in an inactive dephosphorylated state. Chen, D., Fucini, R.V., Olson, A.L., Hemmings, B.A., Pessin, J.E. Mol. Cell. Biol. (1999) [Pubmed]
  27. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCC1). Dowd, B.F., Forbush, B. J. Biol. Chem. (2003) [Pubmed]
  28. Cytoskeletal reorganization internalizes multiple transient receptor potential channels and blocks calcium entry into human neutrophils. Itagaki, K., Kannan, K.B., Singh, B.B., Hauser, C.J. J. Immunol. (2004) [Pubmed]
  29. A role for protein phosphatase-2A in p38 mitogen-activated protein kinase-mediated regulation of the c-Jun NH(2)-terminal kinase pathway in human neutrophils. Avdi, N.J., Malcolm, K.C., Nick, J.A., Worthen, G.S. J. Biol. Chem. (2002) [Pubmed]
  30. Phosphorylation of the histone deacetylase 7 modulates its stability and association with 14-3-3 proteins. Li, X., Song, S., Liu, Y., Ko, S.H., Kao, H.Y. J. Biol. Chem. (2004) [Pubmed]
  31. Regulation of skeletal muscle blood flow during acute insulin-induced hypoglycemia in the rat. Hickner, R.C., Ungerstedt, U., Henriksson, J. Diabetes (1994) [Pubmed]
  32. Protein phosphatase 2C inactivates F-actin binding of human platelet moesin. Hishiya, A., Ohnishi, M., Tamura, S., Nakamura, F. J. Biol. Chem. (1999) [Pubmed]
  33. Inhibition of the iron-induced ZmFer1 maize ferritin gene expression by antioxidants and serine/threonine phosphatase inhibitors. Savino, G., Briat, J.F., Lobréaux, S. J. Biol. Chem. (1997) [Pubmed]
  34. Evidence for protein phosphatase 1 and 2A regulation of K+ channels in two types of leaf cells. Li, W., Luan, S., Schreiber, S.L., Assmann, S.M. Plant Physiol. (1994) [Pubmed]
  35. T cell apoptosis induced by interleukin-2 deprivation or transforming growth factor-beta 2: modulation by the phosphatase inhibitors okadaic acid and calyculin A. Weller, M., Malipiero, U., Groscurth, P., Fontana, A. Exp. Cell Res. (1995) [Pubmed]
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