p190RhoGAP can act to inhibit PDGF-induced gliomas in mice:: a putative tumor suppressor encoded on human chromosome 19q13.3
p190RhoGAP can act to inhibit PDGF-induced gliomas in mice:: a putative tumor suppressor encoded on human chromosome 19q13.3
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DOI：
10.1101/gad.1040003
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发表时间：
2003-02-15
影响因子：
10.5
通讯作者：
Resh, MD
中科院分区：
文献类型：
--
作者：
Wolf, RM;Draghi, N;Resh, MD
p190RhoGAP 和 Rho 是少突胶质细胞分化的关键调节因子。编码 p190RhoGAP 的基因位于人类染色体的 19q13.3，该位点在 50%-80% 的少突胶质细胞瘤中被删除。在这里，我们提供的证据表明 p190RhoGAP 可能通过诱导分化的神经胶质表型来抑制神经胶质瘤发生。使用自分泌环 PDGF 刺激的细胞培养模型，我们发现通过 p190RhoGAP 过表达或 Rho 激酶抑制降低 Rho 活性可诱导细胞过程延伸、增殖受阻以及神经前体标记物巢蛋白表达减少。与单独使用 PDGF 观察到的结果相比，用表达 PDGF 和 p190 GAP 结构域的逆转录病毒体内感染小鼠，导致少突胶质细胞瘤的发生率降低。独立实验表明，50 个 PDGF 诱导的神经胶质瘤中有 3 个的逆转录病毒载体插入位点位于 p190RhoGAP 基因内。这一证据强烈表明 p190 调节 PDGF 肿瘤发生的关键成分，并且可以通过下调 Rho 活性在 PDGF 诱导的神经胶质瘤中充当肿瘤抑制因子。
p190RhoGAP and Rho are key regulators of oligodendrocyte differentiation. The gene encoding p190RhoGAP is located at 19q13.3 of the human chromosome, a locus that is deleted in 50%-80% of oligodendrogliomas. Here we provide evidence that p190RhoGAP may suppress gliomagenesis by inducing a differentiated glial phenotype. Using a cell culture model of autocrine loop PDGF stimulation, we show that reduced Rho activity via p190RhoGAP overexpression or Rho kinase inhibition induced cellular process extension, a block in proliferation, and reduced expression of the neural precursor marker nestin. In vivo infection of mice with retrovirus expressing PDGF and the p190 GAP domain caused a decreased incidence of oligodendrogliomas compared with that observed with PDGF alone. Independent experiments revealed that the retroviral vector insertion site in 3 of 50 PDGF-induced gliomas was within the p190RhoGAP gene. This evidence strongly suggests that p190 regulates critical components of PDGF oncogenesis and can act as a tumor suppressor in PDGF-induced gliomas by down-regulating Rho activity.