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PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis. Blood 2003 Jul 01;102(1):169-79

Date

03/22/2003

Pubmed ID

12649141

DOI

10.1182/blood-2003-01-0003

Scopus ID

2-s2.0-0038508862 (requires institutional sign-in at Scopus site)   112 Citations

Abstract

Programmed cell death, or apoptosis, is a tightly regulated, naturally occurring process by which damaged or unwanted cells are removed. Dysregulated apoptosis has been implicated in a variety of pathophysiological conditions, including degenerative diseases, tissue remodeling, and tumorigenesis. The decision to live or die results from integration of numerous environmental signals transmitted by specific classes of cell surface receptors that bind hormones, growth factors, or components of the extracellular matrix. Here we show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a homophilic-binding member of the immunoreceptor tyrosine-based inhibitory motif (ITIM) family of inhibitory receptors, functions prominently to inhibit apoptosis in naturally occurring vascular cells subjected to apoptotic stimuli. Murine endothelial cells and human T lymphocytes lacking PECAM-1 were found to be far more sensitive than their PECAM-1-expressing counterparts to multiple death signals that stimulate Bax, a multidomain, proapoptotic member of the Bcl-2 family that plays a central role in mitochondrial dysfunction-dependent apoptosis. In addition, PECAM-1 markedly suppressed Bax overexpression-induced cytochrome c release, caspase activation, and nuclear fragmentation. Amino acid substitutions within PECAM-1's extracellular homophilic binding domain, or within its cytoplasmic ITIM, completely abolished PECAM-1-mediated cytoprotection. Taken together, these data implicate PECAM-1 as a novel and potent suppressor of Bax-mediated apoptosis and suggest that members of the immunoglobulin gene (Ig) superfamily, like cell surface integrins, may also transmit survival signals into blood and vascular cells.

Author List

Gao C, Sun W, Christofidou-Solomidou M, Sawada M, Newman DK, Bergom C, Albelda SM, Matsuyama S, Newman PJ

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Caspases
Cell Line
Chickens
Cytochrome c Group
DNA Fragmentation
Endothelium, Vascular
Humans
Intracellular Membranes
Jurkat Cells
Mice
Mice, Knockout
Mitochondria
Platelet Endothelial Cell Adhesion Molecule-1
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
bcl-2-Associated X Protein