© 2001 American Heart Association, Inc.
Molecular Medicine |
xIAP Induces Cell-Cycle Arrest and Activates Nuclear Factor-
B
New Survival Pathways Disabled by Caspase-Mediated Cleavage During Apoptosis of Human Endothelial Cells
From the Institute of Arteriosclerosis Research (B.L., K.K., J.-R.N., G.B.), Department of Pathology (H.A.B.), and Department of Cardiology and Angiology (G.B.), University of Münster, Münster, Germany, and Department of Pathology (K.J.G., N.F., E.W.R.), University of Washington, Seattle, Wash.
Correspondence to Elaine W. Raines, Department of Pathology, Harborview Medical Center, 325 9th Ave, Box 359675, Seattle, WA 98104-2499. E-mail ewraines{at}u.washington.edu
Abstract—Survival
of human vascular endothelial cells depends on their ability to
activate the transcription factor nuclear factor-
B (NF-B), a
regulator of antiapoptotic genes, such as the X chromosome–linked
inhibitor of apoptosis protein (xIAP). In the present study, we
demonstrated expression of xIAP in the endothelial lining of normal
human arteries and veins and elevated levels in highly malignant human
endothelial tumors. Using retroviral infection of human endothelial
cells, we identified two novel survival mechanisms mediated by xIAP in
endothelial cells. First, xIAP can activate the transcription factor
NF-B, a known survival factor for human endothelial cells. This
positive feedback loop induced by xIAP is mediated via phosphorylation
and sustained degradation of inhibitor (I) B
. Second, xIAP
can inhibit cell proliferation via downregulation of cyclins A and D1
and induction of the cyclin-dependent kinase inhibitors
p21Cip1/Waf1 and
p27Kip1. Cleavage of xIAP by caspases during
endothelial cell apoptosis disables both of these biological functions
of xIAP. Thus, caspase-mediated cleavage of xIAP interrupts a positive
regulatory cytoprotective loop between NF-B and xIAP and increases
the vulnerability of the cell to apoptosis by releasing it from an
xIAP-mediated quiescent
state.
Key Words: apoptosis • caspases • cleavage • retrovirus
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