Calmodulin-dependent protein kinase II mediates signal transduction in apoptosis.
The present studies describe a new function for calmodulin-dependent protein kinase II (CaM-KII) in signal transduction leading to apoptosis. Both tumor necrosis factor alpha (TNF) and UV light rapidly stimulated Ca2+-independent activity of CaM-KII in the monocytic leukemia, U937. Two mechanistically different inhibitors of CaM-KII blocked activation of CaM-KII and prevented DNA fragmentation and death. Activation of CaM-KII during apoptosis and inhibition of DNA fragmentation by the two CaM-KII inhibitors were reproduced in several other lines including KGla, HL-60, and YAC-1. However, K562, which is relatively resistant to apoptosis induced by either TNF or UV light, did not activate CaM-KII in response to these stimuli. A variant derived from U937 that is resistant to TNF- or UV light-induced apoptosis also lacked a CaM-KII response. Activation of Cam-KII was blocked by two protease inhibitors, VAD-fmk and TPCK, but not by other inhibitors of serine proteases. Both inhibitors of CaM-KII and the protease inhibitors blocked activation of AP24, a serine protease originally isolated from apoptotic cells that induces DNA fragmentation in nuclei. Our evidence supports a model in which proteolytic activity functions upstream of CaM-KII. This kinase then leads to activation of AP24, which transmits signals to the nucleus to initiate DNA fragmentation.
Wright
S C
SC
The Palo Alto Institute of Molecular Medicine, Mountain View, California 94043, USA.
Schellenberger
U
U
Ji
L
L
Wang
H
H
Larrick
J W
JW
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D006801:Humans; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C108734:AP24 apoptotic protease; D012697:Serine Endopeptidases; D002118:Calcium