Glypican-1 Stimulates Skp2 Autoinduction Loop and G1/S Transition in Endothelial Cells

Qiao, Dianhua; Meyer, Keith; Friedl, Andreas

doi:10.1074/jbc.m111.325282

Cited by 20 publications

(22 citation statements)

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“…Although the precise mechanisms by which D cyclins were downregulated by GPC1 are unclear at this point, this at least suggests that GPC1 did not inactivate the G 1 /S checkpoint via activating cyclin D-CDK4/6. As demonstrated in our previous studies with mouse brain ECs, there are precedents that the cell cycle can be activated independently of D cyclins and mitogens (15). An alternative mechanism for cell cycle activation is offered by the so-called Skp2 autoinduction loop, which consists principally of pRb-E2F, Skp2, p27/p21, and cyclin E/A-CDK2 (22).…”

Section: R E T R a C T E Dmentioning

confidence: 76%

“…U87-MG cells, a human glioblastoma cell line (ATCC HTB-14), were grown on gelatin-coated tissue culture surfaces in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2-mM L-glutamine, 100 units/ml of penicillin/streptomycin, sodium pyruvate, nonessential amino acids, and a vitamin solution (Life Technologies Inc., Rockville, MD). Adenoviral transduction for transient expression of murine GPC1 was performed as described previously (15). For reporter assays, the cells were transiently transfected with Lipofectamine 2000 (Invitrogen, Carlsbad, CA) in the presence of 10% fetal bovine serum (FBS) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…4B). This increased pRb protein degradation might be attributable to hyper- phosphorylation by CDKs as observed in mouse brain ECs transduced by GPC1 (15). Studies have shown that distinct phosphorylation sites exist in pRb and that extraordinarily high CDK2 activity can cause pRb phosphorylation at Ser 567 , which targets pRb to ubiquitin-mediated proteasomal degradation (20).…”

Section: R E T R a C T E Dmentioning

confidence: 97%

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Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes

Qiao

Meyer

Friedl

2013

Molecular and Cellular Biology

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c 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 G 1 /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.

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Section: R E T R a C T E Dmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Section: R E T R a C T E Dmentioning

confidence: 97%

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Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes

Qiao

Meyer

Friedl

2013

Molecular and Cellular Biology

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“…However, in this scenario the signaling activity might also be reduced if FGF2 is sequestered from FGFR1 by the increased levels of GPC1 at the cell surface (Fico et al, 2011;Qiao et al, 2003;Su et al, 2006). Interestingly, in the context of ECs, the knockdown of GPC1 inhibits cell growth, whereas its overexpression can either promote cell proliferation or disrupt cell cycle progression, depending on the expression level of GPC1 (Qiao et al, 2012;Qiao et al, 2008). Taken together, this suggests that the levels of GPC1 need to be tightly regulated in order to ensure the adequate control of cell cycle progression in ECs.…”

Section: Discussionmentioning

confidence: 99%

“…From the set of predicted targets, we selected FGFR1 and GPC1 for further analysis; the rationale for this selection was based on: (1) the well-established role of FGFR1 and its ligand FGF2 in EC angiogenesis (Gerwins et al, 2000;Presta et al, 2005), (2) the role of GPC1 as a low-affinity receptor for FGF (Zhang et al, 2001) that promotes FGF2 binding to its receptor (FGFR1), potentiating FGF signaling (Fico et al, 2011;Filmus et al, 2008;Gerwins et al, 2000;Iozzo and Sanderson, 2011;Presta et al, 2005;Qiao et al, 2003;Su et al, 2006), (3) the fact that GPC1 has been shown to modulate EC proliferation (Qiao et al, 2012;Qiao et al, 2003;Qiao et al, 2008), (4) the finding that FGFR1 regulation by miRNAs negatively controls EC angiogenic functions (Chamorro-Jorganes et al, 2011), (5) the fact that the regulation of host genes by their intronic miRNA has been shown to be biologically relevant (Nikolic et al, 2010) (Megraw et al, 2010), and (6) the finding that these genes showed a relatively high number of predicted binding sites for miR-149 and miR-149* in their 39 untranslated regions (39UTRs). Indeed, miRNA target algorithms found nine binding sites in the FGFR1 39UTR (three for miR-149 and six for miR-149*) and 12 binding sites in the GPC1 39UTR (four for miR-149 and eight for miR-149*) (supplementary material Fig.…”

mentioning

confidence: 99%

Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells

Chamorro-Jorganes

Araldi

Rotllan

et al. 2014

Journal of Cell Science

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MicroRNA-149 (miR-149) is located within the first intron of the glypican-1 (GPC1) gene. GPC1 is a low affinity receptor for fibroblast growth factor (FGF2) that enhances FGF2 binding to its receptor (FGFR1), subsequently promoting FGF2-FGFR1 activation and signaling. Using bioinformatic approaches, both GPC1 and FGFR1 were identified and subsequently validated as targets for miR-149 (both the mature strand, miR-149, and the passenger strand, miR-149*) in endothelial cells (ECs). As a consequence of their targeting activity towards GPC1 and FGFR1, both miR-149 and miR-149* regulated FGF2 signaling and FGF2-induced responses in ECs, namely proliferation, migration and cord formation. Moreover, lentiviral overexpression of miR-149 reduced in vivo tumor-induced neovascularization. Importantly, FGF2 transcriptionally stimulated the expression of miR-149 independently of its host gene, therefore assuring the steady state of FGF2-induced responses through the regulation of the GPC1-FGFR1 binary complex in ECs.

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Boning up on glypicans—opportunities for new insights into bone biology

Dwivedi

Lam

Powell

2013

Cell Biochemistry & Function

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Bone formation is remarkable for the convergence in the activity of four major signalling pathways, the bone morphogenetic protein (BMP), fibroblast growth factor (FGF), hedgehog (HH) and wingless-integrated (WNT) pathways. These pathways cooperate in morphogenetic, proliferative and differentiative processes that underpin the development, growth and repair of skeletal structures. They are regulated by pathway-specific modulators and by another class of molecules, the glypicans. Glypicans are proteoglycans located on the cell surface, where they act as coreceptors to promote or inhibit signalling by ligands of the BMP, FGF, HH and WNT pathways, through protein-protein and protein-carbohydrate interactions. In this review, we discuss glypican structure, expression and function in the context of bone development and growth, with emphasis on the long bone growth plate where five of the six glypicans are expressed in overlapping patterns in the chondrogenic zone. Analyses of gene knockout models and the human conditions of Simpson-Golabi-Behmel syndrome and omodysplasia, which arise from mutations in glypican 3 (GPC3) and GPC6, respectively, highlight both subtle and striking effects of glypicans on bone growth. We draw attention to challenges and areas of opportunity, where the actions of glypicans on BMP, FGF, HH and WNT signalling might be profitably studied to help illuminate the complex interplay of signalling that drives bone growth.

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Glypican-1 Stimulates Skp2 Autoinduction Loop and G1/S Transition in Endothelial Cells

Cited by 20 publications

References 50 publications

Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes

Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes

Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells

Boning up on glypicans—opportunities for new insights into bone biology

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