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J. Biol. Chem., Vol. 278, Issue 19, 17438-17447, May 9, 2003
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From the Departments of Previous studies have
demonstrated that overexpression of GRP78/BiP, an endoplasmic
reticulum (ER)-resident molecular chaperone, in mammalian cells
inhibits the secretion of specific coagulation factors. However, the
effects of GRP78/BiP on activation of the coagulation cascade
leading to thrombin generation are not known. In this study, we
examined whether GRP78/BiP overexpression mediates cell surface
thrombin generation in a human bladder cancer cell line T24/83 having
prothrombotic characteristics. We report here that cells overexpressing
GRP78/BiP exhibited significant decreases in cell surface-mediated
thrombin generation, prothrombin consumption and the formation of
thrombin-inhibitor complexes, compared with wild-type or
vector-transfected cells. This effect was attributed to the ability of
GRP78/BiP to inhibit cell surface tissue factor (TF) procoagulant
activity (PCA) because conversion of factor X to Xa and factor VII to
VIIa were significantly lower on the surface of
GRP78/BiP-overexpressing cells. The additional findings that (i) cell
surface factor Xa generation was inhibited in the absence of factor
VIIa and (ii) TF PCA was inhibited by a neutralizing antibody to human
TF suggests that thrombin generation is mediated exclusively by TF.
GRP78/BiP overexpression did not decrease cell surface levels of TF,
suggesting that the inhibition in TF PCA does not result from retention
of TF in the ER by GRP78/BiP. The additional observations that both
adenovirus-mediated and stable GRP78/BiP overexpression attenuated TF
PCA stimulated by ionomycin or hydrogen peroxide suggest that GRP78/BiP
indirectly alters TF PCA through a mechanism involving cellular
Ca2+ and/or oxidative stress. Similar results were
also observed in human aortic smooth muscle cells transfected with the
GRP78/BiP adenovirus. Taken together, these findings demonstrate
that overexpression of GRP78/BiP decreases thrombin generation by
inhibiting cell surface TF PCA, thereby suppressing the prothrombotic
potential of cells.
Overexpression of the 78-kDa Glucose-regulated
Protein/Immunoglobulin-binding Protein (GRP78/BiP) Inhibits Tissue
Factor Procoagulant Activity*
§,,,,
,,
Pathology and Molecular
Medicine, ¶ Pediatrics, and Medicine, McMaster University
and the Henderson Research Centre, Hamilton, Ontario L8V 1C3 and the
** Division of Experimental Therapeutics, Ontario Cancer
Institute, Toronto, Ontario M5G 2M9, Canada
*
This research was supported in part by Research Grants
NA-4842 (to R. C. A.) and NA4020 (to A. K. C. C.) from the Heart
and Stroke Foundation of Ontario.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
A Career Investigator of the Heart and Stroke Foundation of
Ontario (HSFO). To whom correspondence should be addressed: Henderson Research Centre, 711 Concession St., Hamilton, Ontario L8V 1C3, Canada.
Tel.: 905-527-2299 (ext. 42628); Fax: 905-575-2646; E-mail: raustin@thrombosis.hhscr.org.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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