| 1. |
- Dimberg, Anna, et al.
(författare)
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alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:4, s. 2015-2023
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Tidskriftsartikel (refereegranskat)abstract
- Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alpha B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alpha B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alpha B-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alpha B-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alpha B-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alpha B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of anglogenic modulators.
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| 2. |
- Matsumoto, Taro, et al.
(författare)
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Ninein Is Expressed in the Cytoplasm of Angiogenic Tip-Cells and Regulates Tubular Morphogenesis of Endothelial Cells
- 2008
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 28, s. 2123-2130
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Tidskriftsartikel (refereegranskat)abstract
- Objective— Angiogenesis is an integral part of many physiologicalprocesses but may also aggravate pathological conditions suchas cancer. Development of effective angiogenesis inhibitorsrequires a thorough understanding of the molecular mechanismsregulating vessel formation. The aim of this project was toidentify proteins that regulate tubular morphogenesis of endothelialcells.Methods and Results— Phosphotyrosine-dependent affinity-purificationand mass spectrometry showed tyrosine phosphorylation of nineinduring tubular morphogenesis of endothelial cells. Ninein wasrecently identified as a centrosomal microtubule-anchoring protein.Our results show that ninein is localized in the cytoplasm inendothelial cells, and that it is highly expressed in the vasculaturein normal and pathological human tissues. Using embryoid bodiesas a model of vascular development, we found that ninein isabundantly expressed in the cytoplasm of endothelial cells duringsprouting angiogenesis, in particular in the sprouting tip-cell.In accordance, siRNA-dependent silencing of ninein in endothelialcells inhibited tubular morphogenesis.Conclusions— In this study, we show that ninein is expressedin developing vessels and in endothelial tip cells, and thatninein is critical for formation of the vascular tube. Thesedata strongly implicate ninein as an important new regulatorof angiogenesis.Proteins orchestrating morphological changes accompanying formationof the vascular tube constitute new targets for antiangiogenictherapy. In this study, we identify the microtubule-anchoringprotein ninein as an important new regulator of tubular morphogenesisof endothelial cells. This is the first report of a functionalrole of ninein in angiogenesis.
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| 3. |
- Matsumoto, Taro, et al.
(författare)
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VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis.
- 2005
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Ingår i: EMBO J. - 0261-4189. ; 24:13, s. 2342-53
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor receptor-2 (VEGFR-2) activation by VEGF-A is essential in vasculogenesis and angiogenesis. We have generated a pan-phosphorylation site map of VEGFR-2 and identified one major tyrosine phosphorylation site in the kinase insert (Y951), in addition to two major sites in the C-terminal tail (Y1175 and Y1214). In developing vessels, phosphorylation of Y1175 and Y1214 was detected in all VEGFR-2-expressing endothelial cells, whereas phosphorylation of Y951 was identified in a subset of vessels. Phosphorylated Y951 bound the T-cell-specific adapter (TSAd), which was expressed in tumor vessels. Mutation of Y951 to F and introduction of phosphorylated Y951 peptide or TSAd siRNA into endothelial cells blocked VEGF-A-induced actin stress fibers and migration, but not mitogenesis. Tumor vascularization and growth was reduced in TSAd-deficient mice, indicating a critical role of Y951-TSAd signaling in pathological angiogenesis.
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