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Deeba Husain, Eva Chou, Rosana D. Meyer, Nader Rahimi; Casitase B-lineage Lymphoma (c-Cbl) Pathway Regulates Pathological Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4863.
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c-Cbl has been identified as a negative regulator of PLC gamma 1 in endothelial cells. The biological significance and molecular mechanisms of c-Cbl is not known. This study is designed to study the effect of c-Cbl in three in vivo models of angiogenesis: cell proliferation assay, experimental choroidal neovascularization and tumor-induced angiogenesis model.
Cell proliferation assay: c-Cbl null and wild type microvascular endothelial cells were prepared for in vitro angiogenesis. Cells were either unstimulated (-) or stimulated with VEGF (100ng/ml) and pictures were taken after 16 hours. Experimental choroidal neovascularization: Laser injury model was used in c -Cbl Null mice and wild mice. These eyes were imaged weekly with flourescein angiography for 4 weeks and the data was analyzed. Tumor Angiogenesis: c-Cbl null and wild Mice (4 animals for each experiment) were subcutaneously injected with Matrigel (10mg/ml) plus B16 melanoma cells (1x107). The tumor size was measured every 4 day for 12 days.
We found that loss of c-Cbl in endothelial cells promotes enhanced cell proliferation and angiogenesis in vitro. Loss of c-Cbl in mice leads to robust and sustained choroidal neovascularization. c-Cbl null mice showed larger and rapidly growing tumors.
We propose c-Cbl is an angiogenic suppressor protein where upon activation it uniquely modulates PLC gamma1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis. Therefore this may offer a potential new target in the treatment of angiogenesis related diseases such as exudative macular degeneration.
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