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Calmodulin-dependent protein kinase II mediates signal transduction in apoptosis

Wright, S.C.; Schellenberger, U.; Ji, L.; Wang, H.; Larrick, J.W.

FASEB Journal 11(11): 843-849

1997


ISSN/ISBN: 0892-6638
PMID: 9285482
DOI: 10.1096/fasebj.11.11.9285482
Accession: 008258439

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 Ca-2+-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 KG1a, 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.

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