CALMODULIN-DEPENDENT PROTEIN-KINASE-II MEDIATES SIGNAL-TRANSDUCTION IN APOPTOSIS

The present studies describe a new function for calmodulin-dependent p rotein kinase II (CaM-KII) in signal transduction leading to apoptosis , Both tumor necrosis factor a (TNF) and UV light rapidly stimulated C a2+-independent activity of CaM-KII in the monocytic leukemia, U937, T wo mechanistically different inhibitors of CaM-KII blocked activation of CaM-KII and prevented DNA fragmentation and death, Activation of Ca M-KII during apoptosis and inhibition of DNA fragmentation by the two CaM-KII. inhibitors were reproduced in several other lines including K G1a, 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 res istant to TNF-or UV light-induced apoptosis also lacked a CaM-KII resp onse, Activation of Cam-KII was blocked by two protease inhibitors, VA D-fmk and TPCK, but not by other inhibitors of serine proteases, Both inhibitors of CaM-KII and the protease inhibitors blocked activation o f AP24, a serine protease originally isolated from apoptotic cells tha t induces DNA fragmentation in nuclei, Our evidence supports a model i n which proteolytic activity functions upstream of CaM-KII. This kinas e then leads to activation of AP24, which transmits signals to the nuc leus to initiate DNA fragmentation.