Antiapoptotic effect of coagulation factor VIIa.
Binding of factor VIIa (FVIIa) to its cellular receptor tissue factor (TF) was previously shown to induce various intracellular signaling events, which were thought to be responsible for TF-mediated biologic effects, including angiogenesis, tumor metastasis, and restenosis. To understand the mechanisms behind these processes, we have examined the effect of FVIIa on apoptosis. Serum deprivation-induced apoptosis of BHK(+TF) cells was characterized by apoptotic blebs, nuclei with chromatin-condensed bodies, DNA degradation, and activation of caspase 3. FVIIa markedly decreased the number of cells with apoptotic morphology and prevented the DNA degradation as measured by means of TdT-mediated dUTP nick end labeling (TUNEL). The antiapoptotic effect of FVIIa was confirmed by the observation that FVIIa attenuated caspase 3 activation. FVIIa-induced antiapoptotic effect was dependent on its proteolytic activity and TF but independent of factor Xa and thrombin. FVIIa-induced cell survival correlated with the activation of Akt and was inhibited markedly by the specific PI3-kinase inhibitor, LY294002. Blocking the activation of p44/42 mitogen-activated protein kinase (MAPK) by the specific mitogen-induced extracellular kinase (MEK) inhibitor, U0126, impaired modestly the ability of FVIIa to promote cell survival. In conclusion, FVIIa binding to TF provided protection against apoptosis induced by growth factor deprivation, primarily through activation of PI3-kinase/Akt pathway, and to a lesser extent, p44/42 MAPK pathway.
Novo Nordisk, Hemostasis Biology, Novo Nordisk Park C9-1.27, DK-2760 Maaloev, Denmark. bbsn@novonordisk.com
Brit B
BB
Sorensen
L Vijaya Mohan
LV
Rao
Ditte
D
Tornehave
Steen
S
Gammeltoft
Lars C
LC
Petersen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001798:Blood Proteins / Q000494:pharmacology; D016466:CHO Cells; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D015942:Factor VIIa / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013925:Thromboplastin / Q000378:metabolism
D001798:Blood Proteins; D053148:Caspase 3; D020169:Caspases; D015942:Factor VIIa; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013925:Thromboplastin; C494918:AKT1 protein, human; C505407:CASP3 protein, human