Ca2+/calmodulin-dependent protein kinase II is required for microcystin-induced apoptosis.
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 Ca(2+)/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.
Fladmark
Kari E
KE
Department of Anatomy and Cell Biology, University of Bergen, Arstadveien 19, N-5009 Bergen, Norway.
Brustugun
Odd T
OT
Mellgren
Gunnar
G
Krakstad
Camilla
C
Boe
Roald
R
Vintermyr
Olav K
OK
Schulman
Howard
H
Doskeland
Stein O
SO
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes; D006801:Humans; D020128:Inhibitory Concentration 50; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D051379:Mice; D052998:Microcystins; D008856:Microscopy, Fluorescence; D019319:Okadaic Acid / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014162:Transfection
D004791:Enzyme Inhibitors; D007476:Ionophores; D052998:Microcystins; D010456:Peptides, Cyclic; C063998:nodularin; D019319:Okadaic Acid; D004441:Ecdysterone; C078588:microcystin; C008999:ponasterone A; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases