title: Tissue factor/factor VIIa induces cell survival and gene transcription by transactivation of the insulin-like growth factor 1 receptor.
abstract: The insulin-like growth factor 1 receptor (IGF-1R) is known to promote survival and has also been implicated in the pathogenesis of several disease states, including cardiovascular disorders and cancer. Recently, we showed that binding of coagulation factor VIIa (FVIIa) to its receptor tissue factor (TF) protects cancer cells from TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. Here we present evidence that this biological function of TF/FVIIa is dependent on the IGF-1R. IGF-1R inhibitors AG1024 and PPP as well as siRNA-mediated downregulation of IGF-1R, abolished the TF/FVIIa-mediated protection against TRAIL-induced apoptosis. Moreover, FVIIa rapidly induced a time- and concentration-dependent tyrosine phosphorylation of the IGF-1R in MDA-MB-231 breast cancer cells and in primary human monocytes, an event that was accompanied by IGF-1R chromatin binding and gene transcription. We hereby present novel evidence of a cross-talk between the coagulation and IGF-1R signalling systems, and propose that the IGF-1R is a key player in mediating TF/FVIIa-induced cell survival.
authors: Mikael
authors: M
authors: Åberg
authors: Oskar
authors: O
authors: Eriksson
authors: Dariush
authors: D
authors: Mokhtari
authors: Prof. Agneta Siegbahn, MD, PhD, FESC, Department of Medical Sciences, Clinical Chemistry and Science for Life Laboratory, University Hospital, Entr. 61 3rd floor, S-751 85 Uppsala, Sweden, E-mail: agneta.siegbahn@medsci.uu.se, Tel.: +46 186114251, Fax: +46 18552562.
authors: Agneta
authors: A
authors: Siegbahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D015942:Factor VIIa / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C412835:2-phenyl-2-(1-piperidinyl)propane; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D013925:Thromboplastin; D017526:Receptor, IGF Type 1; D015942:Factor VIIa; D010622:Phencyclidine
keywords: Apoptosis; Cell signalling; FVIIa; IGF-1R; Tissue factor