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From the Department of Internal Medicine IV, Division of Molecular Cardiology, University of Frankfurt, 60590 Frankfurt, Germany

Injury of the endothelial cells by the induction of apoptotic cell death may play an important role in the pathophysiology of atherosclerosis and the progression of inflammatory diseases. Here, we demonstrate an essential role for the ubiquitin-dependent proteasome complex in stimulus-induced degradation of the antiapoptotic protein Bcl-2. Bcl-2 is specifically degraded after stimulation of human endothelial cells with tumor necrosis factor (TNF)- in a process that is inhibited by specific proteasome inhibitors. In addition, the mutation of the potential ubiquitin-acceptor amino acids of Bcl-2 provides protection against TNF-– and staurosporine-induced degradation in vitro and in vivo. Moreover, mimicking phosphorylation of the putative mitogen-activated protein (MAP) kinase sites of the Bcl-2 protein (Thr 56, Thr 74, and Ser 87) abolishes its degradation, suggesting a link between the MAP kinase pathway to the proteasome pathway. Finally, inhibition of Bcl-2 degradation either by suppressing ubiquitin-dependent proteasomal degradation or by mimicking continuous phosphorylation of the putative MAP kinase sites in the Bcl-2 protein confers resistance against induction of apoptosis. Thus, the degradation of Bcl-2 may unleash the inhibitory function of Bcl-2 over the apoptosome and may thereby amplify the activation of the caspase cascade.

Key Words: Bcl-2 • apoptosis • mitogen-activated protein kinase • endothelial cells • proteasome

Abbreviations used: ALLN, N-acetyl-leucinyl-leucinyl-norleucinal-H; Ced, Caenorhabditis elegans cell death gene; ERK, extracellular signal–regulated kinase; HUVEC, human umbilical vein endothelial cell; MAP, mitogen-activated protein; MKP, mitogen-activated protein kinase phosphatase; Z-LLL-H, carbobenzoxyl-leucinyl-leucinyl-leucinal-H.

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