Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes (Retracted article. See vol. 36, pg. 2105, 2016)
Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes (Retracted article. See vol. 36, pg. 2105, 2016)
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DOI：
10.1128/mcb.00238-13
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发表时间：
2013-11-01
影响因子：
5.3
通讯作者：
Friedl, Andreas
中科院分区：
文献类型：
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作者：
Qiao, Dianhua;Meyer, Kristy;Friedl, Andreas
恶性神经胶质瘤是一种高度致命的肿瘤，治疗选择有限。我们以前发现硫酸乙酰肝素蛋白聚糖磷脂酰肌醇蛋白聚糖1（GPC 1）是普遍和高度表达在人类胶质瘤。在这项研究中，我们研究了GPC 1表达的生物学活性在人类胶质瘤细胞和正常星形胶质细胞在体外。GPC 1的表达使G（1）/S检查点失活并强烈刺激DNA复制。GPC 1的组成型表达引起DNA再复制和DNA损伤，表明GPC 1具有致突变活性。GPC 1表达导致肿瘤抑制因子pRb、Cip/Kip细胞周期蛋白依赖性激酶抑制剂（CKIs）和CDH 1的显著下调，以及促癌蛋白细胞周期蛋白E、细胞周期蛋白依赖性激酶2（CDK 2）、Skp 2和Cdt 1的上调。这些GPC 1诱导的变化伴随着所有类型的D细胞周期蛋白的显着减少，这是独立的血清补充。GPC 1可能刺激所谓的Skp 2自诱导环，而不依赖于细胞周期蛋白D-CDK 4/6。敲低Skp 2，CDK 2，或细胞周期蛋白E，三个关键元素内的网络由GPC 1调制，结果在减少的S期和非整倍体分数，这意味着这些监管机构在GPC 1诱导的S期进入和DNA再复制的功能作用。此外，在正常人星形胶质细胞中，即使在生长因子补充剂存在下，GPC 1也可显著激活细胞外信号调节激酶（ERK）/促分裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路。这两种途径在人类神经胶质瘤中被组成性激活。GPC 1对细胞周期的影响的惊人的幅度和促有丝分裂和致突变的性质意味着GPC 1可能在胶质瘤肿瘤发生和生长中起重要作用。
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.