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Originally published as MBC in Press, 10.1091/mbc.E07-10-1025 on April 30, 2008 Originally published as MBC in Press, 10.1091/mbc.E07-10-1025 on April 16, 2008

Vol. 19, Issue 7, 2789-2801, July 2008

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Glypican-1 Regulates Anaphase Promoting Complex/Cyclosome Substrates and Cell Cycle Progression in Endothelial Cells

Dianhua Qiao*, Xinhai Yang*, Kristy Meyer*, and Andreas Friedl*,{dagger}

*Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792; and {dagger}Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Madison, WI 53705

Submitted October 10, 2007; Revised March 24, 2008; Accepted April 9, 2008
Monitoring Editor: Richard Assoian

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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-10-1025) on April 30, 2008.

Address correspondence to: Andreas Friedl (afriedl{at}wisc.edu)

Abbreviations used: APC/C, anaphase promoting complex/cyclosome; BMVEC, brain microvascular endothelial cell; CDK, cyclin-dependent kinase; dally, division abnormally delayed; EC, endothelial cell; GPC, glypican; HS, heparan sulfate; HSPG, heparan sulfate proteoglycan; PKA, protein kinase A; SCF, Skp1-Cullin-F-box protein complex; SDC1, syndecan-1; shRNA, small hairpin RNA.






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