Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-06-27

AUTHORS

M N Koenig, E Naik, L Rohrbeck, M J Herold, E Trounson, P Bouillet, T Thomas, A K Voss, A Strasser, L Coultas

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. More... »

PAGES

1687-1695

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cdd.2014.90

DOI

http://dx.doi.org/10.1038/cdd.2014.90

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24971484


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31 schema:description 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.
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38 BIM
39 BIM mRNA levels
40 Bim mRNA
41 Bim promoter
42 FOXO
43 FOXO3
44 Recent studies
45 VEGF
46 angiogenesis
47 anti-angiogenic effects
48 apoptosis
49 blood vessels
50 cell apoptosis
51 cell death independent
52 cell-autonomous role
53 cells
54 certain tumor models
55 cluster miRNAs
56 clusters
57 conditions
58 conflict
59 death
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61 development
62 disease
63 downregulation
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65 effect
66 endothelial apoptosis
67 endothelial cell apoptosis
68 endothelial cells
69 endothelial death
70 essential initiator
71 evidence
72 extent
73 factor withdrawal
74 factors
75 function
76 growth
77 growth factor
78 growth factor withdrawal
79 importance
80 independent
81 inhibitors
82 initiator
83 levels
84 mRNA
85 mRNA levels
86 miR
87 miRNAs
88 mice
89 model
90 new blood vessels
91 normal development
92 numerous diseases
93 pathology
94 primary endothelial cells
95 pro-apoptotic BCL2 family proteins
96 pro-apoptotic Bim
97 promoter
98 protein
99 regulation
100 response
101 role
102 serum
103 sites
104 steady-state conditions
105 study
106 such conditions
107 transcription factor FOXO3
108 tumor model
109 vessels
110 vivo
111 withdrawal
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