title: Glypican 1 stimulates S phase entry and DNA replication in human glioma cells and normal astrocytes.
abstract: Malignant gliomas are highly lethal neoplasms with limited treatment options. We previously found that the heparan sulfate proteoglycan glypican 1 (GPC1) is universally and highly expressed in human gliomas. In this study, we investigated the biological activity of GPC1 expression in both human glioma cells and normal astrocytes in vitro. Expression of GPC1 inactivates the G1/S checkpoint and strongly stimulates DNA replication. Constitutive expression of GPC1 causes DNA rereplication and DNA damage, suggesting a mutagenic activity for GPC1. GPC1 expression leads to a significant downregulation of the tumor suppressors pRb, Cip/Kip cyclin-dependent kinase inhibitors (CKIs), and CDH1, and upregulation of the pro-oncogenic proteins cyclin E, cyclin-dependent kinase 2 (CDK2), Skp2, and Cdt1. These GPC1-induced changes are accompanied by a significant reduction in all types of D cyclins, which is independent of serum supplementation. It is likely that GPC1 stimulates the so-called Skp2 autoinduction loop, independent of cyclin D-CDK4/6. Knockdown of Skp2, CDK2, or cyclin E, three key elements within the network modulated by GPC1, results in a reduction of the S phase and aneuploid fractions, implying a functional role for these regulators in GPC1-induced S phase entry and DNA rereplication. In addition, a significant activation of both the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways by GPC1 is seen in normal human astrocytes even in the presence of growth factor supplement. Both pathways are constitutively activated in human gliomas. The surprising magnitude and the mitogenic and mutagenic nature of the effect exerted by GPC1 on the cell cycle imply that GPC1 may play an important role in both glioma tumorigenesis and growth.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Dianhua
authors.initials: D
authors.lastname: Qiao
authors.forename: Kristy
authors.initials: K
authors.lastname: Meyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Friedl
mesh_terms: D000782:Aneuploidy; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D056741:Cyclin D / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004261:DNA Replication; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016196:S Phase
chemical_list: D056741:Cyclin D; D053673:Glypicans; D004247:DNA; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
references.citation: Nat Rev Cancer. 2009 Mar;9(3):153-66
references.pmid: 19238148
references.citation: Br J Cancer. 2004 Apr 19;90(8):1606-11
references.pmid: 15083193
references.citation: Radiat Res. 2003 Aug;160(2):217-23
references.pmid: 12859233
references.citation: Annu Rev Pharmacol Toxicol. 1999;39:295-312
references.pmid: 10331086
references.citation: Mol Cell. 2003 Apr;11(4):997-1008
references.pmid: 12718885
references.citation: Oncogene. 2008 Feb 7;27(7):907-17
references.pmid: 17700535
references.citation: Trends Cell Biol. 2012 Jan;22(1):33-41
references.pmid: 22154077
references.citation: J Biol Chem. 2012 Feb 17;287(8):5898-909
references.pmid: 22203671
references.citation: J Mol Cell Biol. 2011 Feb;3(1):13-22
references.pmid: 21278447
references.citation: Cancer Res. 2004 Oct 1;64(19):7011-21
references.pmid: 15466194
references.citation: Am J Pathol. 2006 Jun;168(6):2014-26
references.pmid: 16723715
references.citation: Nat Genet. 2000 May;25(1):55-7
references.pmid: 10802656
references.citation: Gene. 1998 Jan 12;206(2):255-61
references.pmid: 9469940
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6242-4
references.pmid: 10841526
references.citation: Bioessays. 2005 Apr;27(4):408-15
references.pmid: 15770681
references.citation: Cancer Res. 2011 Jun 15;71(12):4055-60
references.pmid: 21628493
references.citation: Cell Mol Life Sci. 2004 May;61(9):1016-24
references.pmid: 15112050
references.citation: Curr Biol. 2002 Oct 29;12(21):1817-27
references.pmid: 12419181
references.citation: Biol Chem. 2000 Sep-Oct;381(9-10):827-38
references.pmid: 11076015
references.citation: Cancer Res. 1999 Feb 15;59(4):807-10
references.pmid: 10029067
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Oncogene. 2005 Dec 8;24(55):8176-86
references.pmid: 16261166
references.citation: Nature. 2008 Oct 23;455(7216):1129-33
references.pmid: 18948956
references.citation: J Cell Biol. 2007 Aug 27;178(5):741-7
references.pmid: 17724117
references.citation: Nature. 2004 Aug 12;430(7001):797-802
references.pmid: 15306814
references.citation: Oncogene. 2005 Jan 13;24(3):314-25
references.pmid: 15678131
references.citation: Glia. 2011 Aug;59(8):1135-47
references.pmid: 21351156
references.citation: J Cell Biol. 1997 Nov 17;139(4):851-64
references.pmid: 9362504
references.citation: FEBS Lett. 2012 Aug 31;586(18):2803-12
references.pmid: 22841721
references.citation: Nat Cell Biol. 2008 Jul;10(7):802-11
references.pmid: 18552834
references.citation: Curr Biol. 2004 Sep 21;14(18):R787-96
references.pmid: 15380093
references.citation: Cancer Cell. 2005 Jul;8(1):35-47
references.pmid: 16023597
references.citation: Nat Rev Cancer. 2010 May;10(5):319-31
references.pmid: 20414201
references.citation: Semin Cell Dev Biol. 2005 Jun;16(3):323-33
references.pmid: 15840441
references.citation: Genes Dev. 2007 Nov 1;21(21):2683-710
references.pmid: 17974913
references.citation: Annu Rev Genet. 2007;41:237-80
references.pmid: 17630848
references.citation: Cell Cycle. 2007 Jul 1;6(13):1549-52
references.pmid: 17598984
references.citation: Mol Cell. 2006 Nov 3;24(3):433-43
references.pmid: 17081992
references.citation: Cell Mol Life Sci. 2011 Mar;68(6):923-9
references.pmid: 18087675
references.citation: Dev Dyn. 1998 Jan;211(1):72-87
references.pmid: 9438425
references.citation: Neural Dev. 2009 Sep 04;4:33
references.pmid: 19732411
references.citation: J Biol Chem. 2003 May 23;278(21):19358-66
references.pmid: 12646568
references.citation: N Engl J Med. 2008 Jul 31;359(5):492-507
references.pmid: 18669428
references.citation: Brain Pathol. 2009 Jan;19(1):132-43
references.pmid: 19076778
references.citation: Brain Pathol. 1999 Oct;9(4):627-37
references.pmid: 10517501