Activation of the p38 and JNK/SAPK mitogen-activated protein kinase pathways during apoptosis is mediated by a novel retinoid

6-[3-(1-Adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel retinoid which induces apoptosis in the retinoic acid-resistant HL-60R human leukemia cell line. CD437-mediated poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis of HL-GOR cells does not require gene transc ription or protein synthesis since it occurs in the presence or absence of either actinomycin D or cycloheximide. Marked activation of both the p38 an d the JNK/SAPK serine and threonine kinases occurs at 1 h of exposure to CD 437 with subsequent PARP cleavage at 2 h and apoptosis noted at 4 to 6 h, C D437 concentrations as little as 10 nM result in p38 activation and apoptos is of HL-GOR cells. However, inhibition of p38 activation utilizing the spe cific inhibitor SB203580 does not block CD437-mediated PARP cleavage or apo ptosis. In addition, p38 activation is dependent upon the activation of the caspase system since p38 activation is blocked by the pan ICE inhibitor Z- VAD fmk, which also inhibits CD437-mediated apoptosis and PARP cleavage in these cells. CD437-mediated activation of JNK/SAPK is not inhibited by Z-VA D fmk, suggesting that it lies upstream of CD437 activation of caspase acti vity and subsequent apoptosis. The role of JNK/SAPK activation in CD437-med iated apoptosis remains to be defined. (C) 1999 Academic Press.