J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/02/481/10 $2.00
Volume 185 February 1997 481-490

Cytokine Response Modifier A (CrmA) Inhibits Ceramide Formation in Response to Tumor Necrosis Factor (TNF)-: CrmA and Bcl-2 Target Distinct Components in the Apoptotic Pathway

By Ghassan S. Dbaibo,^* David K. Perry, Chris J. Gamard, Rheanna Platt, Guy G. Poirier, Lina M. Obeid,^¶ and Yusuf A. Hannun^¶

From the ^* Department of Pediatrics,  Department of Medicine, and ^¶ Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710; and the Laboratory of Molecular Endocrinology, Laval University, Sainte-Foy, Quebec, G1V-4G2, Canada

Proteases are now firmly established as major regulators of the "execution" phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor- (TNF-)-induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1 converting enzyme and related proteases, inhibited ceramide generation and prevented TNF--induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-B by TNF-, demonstrating that other signaling functions of TNF- remain intact and that ceramide does not play a role in the activation of NF-B. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.

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