Role of c-jun in human myeloid leukemia cell apoptosis induced by pharmacological inhibitors of protein kinase C

AJ Freemerman, AJ Turner, MJ Birrer, E Szabo, K Valerie and S Grant

Department of Medicine, Medical College of Virginia, Richmond 23298, USA.

Recent study results suggest that protein kinase C [PKC (EC 3.1.4.3)] - dependent up-regulation of c-jun may be involved in leukemic cell programmed cell death, or apoptosis, occurring in response to various chemotherapeutic agents. The current study was undertaken to further evaluate the contribution of c-jun in apoptosis with the use of two highly specific pharmacological inhibitors of PKC (calphostin C and chelerythrine). To address this issue, two human leukemic cell lines, HL-60 and U937, and a U937 subline stably expressing a dominant negative c-jun mutant (TAM67) were exposed to calphostin C and chelerythrine, and c-jun expression was monitored at both the mRNA and protein levels. Both PKC inhibitors induced the classic morphological features of apoptosis as well as internucleosomal DNA degradation in a concentration- and schedule-dependent manner. Concomitant with these changes, unequivocal increases were observed in c-jun mRNA (U937 and HL- 60) and protein (U937). In contrast, up-regulation of c-jun mRNA and protein in TAM67-expressing cells exposed to both PKC inhibitors was markedly attenuated relative to effects observed in parental U937 cells. Importantly, despite impaired up-regulation of c-jun at both the message and protein levels, TAM67-expressing cells were equally susceptible to PKC inhibitor-induced apoptosis as parental and empty vector U937 cells. Collectively, these findings raise the possibility that c-jun up-regulation in human myeloid leukemia cells undergoing PKC inhibitor-associated apoptosis represents a response to, rather than a cause of, apoptotic events. They further suggest that this phenomenon involves pathways that do not require PKC activation.

Volume 49, Issue 5, pp. 788-795, 05/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

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