Glypican-1 regulates anaphase promoting complex/cyclosome substrates and cell cycle progression in endothelial cells

Glypican-1 (GPC1), a member of the mammalian glypican family of heparan sulfate proteoglycans, is highly expressed in glioma blood vessel endothelial cells (ECs). In this study, we investigated the role of GPC1 in EC replication by manipulating GPC1 expression in cultured mouse brain ECs. Moderate G...

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Bibliographic Details
Published in:Molecular biology of the cell 2008-07, Vol.19 (7), p.2789-2801
Main Authors: Qiao, Dianhua, Yang, Xinhai, Meyer, Kristy, Friedl, Andreas
Format: Article
Language:English
Subjects:
Anaphase-Promoting Complex-Cyclosome
Animals
Brain - blood supply
Brain - metabolism
Carrier Proteins - physiology
Cell Cycle
Cyclin A - metabolism
Cyclin B - metabolism
Cyclin B1
Endothelial Cells - metabolism
Flow Cytometry - methods
Glypicans - biosynthesis
Glypicans - physiology
Mice
Mitosis
Models, Biological
Neovascularization, Pathologic
Securin
Ubiquitin-Protein Ligase Complexes - metabolism
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Summary:Glypican-1 (GPC1), a member of the mammalian glypican family of heparan sulfate proteoglycans, is highly expressed in glioma blood vessel endothelial cells (ECs). In this study, we investigated the role of GPC1 in EC replication by manipulating GPC1 expression in cultured mouse brain ECs. Moderate GPC1 overexpression stimulates EC growth, but proliferation is significantly suppressed when GPC1 expression is either knocked down or the molecule is highly overexpressed. Flow cytometric and biochemical analyses show that high or low expression of GPC1 causes cell cycle arrest at mitosis or the G2 phase of the cell cycle, accompanied by endoreduplication and consequently polyploidization. We further show that GPC1 inhibits the anaphase-promoting complex/cyclosome (APC/C)-mediated degradation of mitotic cyclins and securin. High levels of GPC1 induce metaphase arrest and centrosome overproduction, alterations that are mimicked by overexpression of cyclin B1 and cyclin A, respectively. These observations suggest that GPC1 regulates EC cell cycle progression at least partially by modulating APC/C-mediated degradation of mitotic cyclins and securin.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E07-10-1025