title: Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3.
abstract: The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim(-/-) primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17∼92 cluster. Bim mRNA levels were also elevated in miR-17∼92(+/-) endothelial cells cultured under steady-state conditions, suggesting that miR-17∼92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells.
authors: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: M N
authors: MN
authors: Koenig
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: E
authors: E
authors: Naik
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: L
authors: L
authors: Rohrbeck
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: M J
authors: MJ
authors: Herold
authors: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: E
authors: E
authors: Trounson
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: P
authors: P
authors: Bouillet
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: T
authors: T
authors: Thomas
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: A K
authors: AK
authors: Voss
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: A
authors: A
authors: Strasser
authors: 1] The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: L
authors: L
authors: Coultas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D042783:Endothelial Cells / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger