Elsevier

Experimental Cell Research

Volume 247, Issue 1, 25 February 1999, Pages 233-240
Experimental Cell Research

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

https://doi.org/10.1006/excr.1998.4350Get rights and content

Abstract

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.

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  • Cited by (0)

    This work was supported in part by the Medical Research Services of the Department of Veterans Affairs (J.A.F.) and National Institutes of Health Grants CA63335 (J.A.F.) and PO1CA51993 (J.A.F., M.I.D.).

    2

    To whom reprint requests should be addressed at the John D. Dingell Medical Center, Oncology (111G), 4646 John R. Street, Detroit, MI 48201-1932.

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