Activation of the p38 and JNK/SAPK Mitogen-Activated Protein Kinase Pathways during Apoptosis Is Mediated by a Novel Retinoid

• Published in: Experimental cell research Vol. 247; no. 1; pp. 233 - 240
• Main Authors: Zhang, Yuxiang, Huang, Ying, Rishi, Arun K., Sheikh, M.Saeed, Shroot, Braham, Reichert, Uve, Dawson, Marcia, Poirier, Guy G., Fontana, Joseph A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.1999
• Subjects: Apoptosis - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Caspases - metabolism; Enzyme Activation - drug effects; Humans; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Mitogen-Activated Protein Kinases; Neoplasm Proteins - biosynthesis; p38 Mitogen-Activated Protein Kinases; Retinoids - pharmacology; RNA, Neoplasm - biosynthesis; Tumor Cells, Cultured
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1006/excr.1998.4350

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-60R cells does not require gene transcription or protein synthesis since it occurs in the presence or absence of either actinomycin D or cycloheximide. Marked activation of both the p38 and the JNK/SAPK serine and threonine kinases occurs at 1 h of exposure to CD437 with subsequent PARP cleavage at 2 h and apoptosis noted at 4 to 6 h. CD437 concentrations as little as 10 nM result in p38 activation and apoptosis of HL-60R cells. However, inhibition of p38 activation utilizing the specific inhibitor SB203580 does not block CD437-mediated PARP cleavage or apoptosis. 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-VAD fmk, suggesting that it lies upstream of CD437 activation of caspase activity and subsequent apoptosis. The role of JNK/SAPK activation in CD437-mediated apoptosis remains to be defined.