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Coagulation factor Xa drives tumor cells into apoptosis through BH3-only protein Bim up-regulation.

Abstract：

:Coagulation Factor (F)Xa is a serine protease that plays a crucial role during blood coagulation by converting prothrombin into active thrombin. Recently, however, it emerged that besides this role in coagulation, FXa induces intracellular signaling leading to different cellular effects. Here, we show that coagulation factor (F)Xa drives tumor cells of epithelial origin, but not endothelial cells or monocytes, into apoptosis, whereas it even enhances fibroblast survival. FXa signals through the protease activated receptor (PAR)-1 to activate extracellular-signal regulated kinase (ERK) 1/2 and p38. This activation is associated with phosphorylation of the transcription factor CREB, and in tumor cells with up-regulation of the BH3-only pro-apoptotic protein Bim, leading to caspase-3 cleavage, the main hallmark of apoptosis. Transfection of tumor cells with dominant negative forms of CREB or siRNA for either PAR-1, Bim, ERK1 and/or p38 inhibited the pro-apoptotic effect of FXa. In fibroblasts, FXa-induced PAR-1 activation leads to down-regulation of Bim and pre-treatment with PAR-1 or Bim siRNA abolishes proliferation. We thus provide evidence that beyond its role in blood coagulation, FXa plays a key role in cellular processes in which Bim is the central player in determining cell survival.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Borensztajn KS,Bijlsma MF,Groot AP,Brüggemann LW,Versteeg HH,Reitsma PH,Peppelenbosch MP,Spek CA

doi

10.1016/j.yexcr.2007.04.014

subject

Has Abstract

pub_date

2007-07-15 00:00:00

pages

2622-33

issue

12

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(07)00187-5

journal_volume

313

pub_type

杂志文章

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