c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin
| Autor: | Melissa Millard, Jingying Xu, Anat Erdreich-Epstein, Orla T. Cox, Xiuhai Ren |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Programmed cell death
Immunology Integrin Apoptosis Genes abl Biology Biochemistry Culture Media Serum-Free Neuroblastoma Vascular Biology Cell Line Tumor hemic and lymphatic diseases Cell Adhesion Animals Humans Receptors Vitronectin RNA Small Interfering Proto-Oncogene Proteins c-abl Cell adhesion Cell Shape Membrane Potential Mitochondrial Integrin alphaVbeta3 Endothelial Cells Cell Biology Hematology Bridged Bicyclo Compounds Heterocyclic Fetal Blood Actin cytoskeleton Actins Culture Media Actin Cytoskeleton Imatinib mesylate biology.protein Cancer research Thiazolidines Cattle RNA Interference Vitronectin Glioblastoma Tyrosine kinase Medulloblastoma |
| Zdroj: | Blood. 115:2709-2718 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Inhibition of integrins αvβ3 and αvβ5 in human brain microvascular endothelial cells (HBMECs) by the function-blocking peptide RGDfV induces loss of spreading on vitronectin, cell detachment, and apoptosis. We demonstrate that cell detachment is not required for apoptosis because plating on bovine serum albumin–blocked poly-L-lysine (allows attachment, but not integrin ligation and cell spreading) also induced apoptosis. Latrunculin B (LatB), which inhibits F-actin polymerization, induced transient loss of HBMEC spreading on vitronectin, but not their detachment, and induced apoptosis despite recovery of cell spreading. However, LatB did not cause apoptosis in 5 tumor cell lines. In HBMECs, both LatB and RGDfV induced transient Y412 and Y245 phosphorylation of endogenous c-Abl, a nonreceptor tyrosine kinase that reciprocally regulates F-actin. LatB also induced nuclear translocation of c-Abl in HBMECs. STI-571 (imatinib), a targeted therapy for BCR-ABL1+ leukemias and inhibitor of c-Abl, platelet-derived growth factor receptor, and c-Kit, decreased endothelial apoptosis. LatB-induced HBMEC apoptosis, and its inhibition by STI-571 also occurred in a 3-dimensional collagen model, supporting physiologic relevance. Last, siRNA to c-Abl (but not nonspecific siRNA) also inhibited RGDfV- and LatB-induced apoptosis. Thus, endogenous c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3/αvβ5 or by LatB-induced disruption of F-actin. |
| Databáze: | OpenAIRE |
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