Journal of Biological Chemistry
Volume 277, Issue 4, 25 January 2002, Pages 2804-2811
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MECHANISMS OF SIGNAL TRANSDUCTION
Ca2+/Calmodulin-dependent Protein Kinase II Is Required for Microcystin-induced Apoptosis*

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The potent natural toxins microcystin, nodularin, and okadaic acid act rapidly to induce apoptotic cell death. Here we show that the apoptosis correlates with protein phosphorylation events and can be blocked by protein kinase inhibitors directed against the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII). The inhibitors used comprised a battery of cell-permeable protein kinase antagonists and CaMKII-directed peptide inhibitors introduced by microinjection or enforced expression. Furthermore, apoptosis could be induced by enforced expression of active forms of CaMKII but not with inactive CaMKII. It is concluded that the apoptogenic toxins, presumably through their known ability to inhibit serine/threonine protein phosphatases, can cause CaMKII-dependent phosphorylation events leading to cell death.

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Published, JBC Papers in Press, November 16, 2001, DOI 10.1074/jbc.M109049200

*

The work was supported by the Norwegian Research Council, the Norwegian Cancer Society, the Novo Nordic Foundation, and the Marine Science and Technology (MAST III) Program of the European Commission.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.