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Toxins 2012, 4(10), 940-954; doi:10.3390/toxins4100940
Article

Calyculin A from Discodermia Calyx Is a Dual Action Toxin that Blocks Calcium Influx and Inhibits Protein Ser/Thr Phosphatases

1,2
 and
1,2,*
1 Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, VA 22908, USA 2 Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22910, USA
* Author to whom correspondence should be addressed.
Received: 11 September 2012 / Revised: 17 October 2012 / Accepted: 17 October 2012 / Published: 22 October 2012
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Abstract

Calyculin A (Caly A) is cell permeable toxin widely used in cell biology research as an inhibitor of type 1 and type 2A protein Ser/Thr phosphatases of the PPP family. Here we tested effects of low concentrations of Caly A on proliferation of human cancer and non-cancer cell lines. We found that long-term 0.3 nM Caly A prevented G1 to S phase cell cycle progression in human Hs-68 fibroblasts and ARPE19 epithelial cells, but not human breast cancer MDA-MB-468, MDA-MB-231 and MCF7 cells. These conditions produced no change in cyclin D1 levels or in the phosphorylation of endogenous proteins. However, acute application of 0.3 nM Caly A blocked serum-induced increase in intracellular calcium levels in Hs-68 fibroblasts, but not in MDA-MB-468 breast cancer cells. We propose that subnanomolar Caly A prevents cell cycle progression because it blocks calcium uptake by fibroblasts. This probably involves non-selective cation channels and cancer cell proliferation was not affected because calcium enters these cells by other channels. Our results suggest that calyculin A has dual actions and acts as a channel blocker, in addition to its well-established effects as a phosphatase inhibitor.
Keywords: phosphatases PP1; PP2A; cyclin D1; calcium channels; cell cycle; MDA-MB-231; MDA-MB-468; MCF-7; ARPE-19 phosphatases PP1; PP2A; cyclin D1; calcium channels; cell cycle; MDA-MB-231; MDA-MB-468; MCF-7; ARPE-19
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Holy, M.; Brautigan, D.L. Calyculin A from Discodermia Calyx Is a Dual Action Toxin that Blocks Calcium Influx and Inhibits Protein Ser/Thr Phosphatases. Toxins 2012, 4, 940-954.

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