Scatter factor/hepatocyte growth factor stimulation of glioblastoma cell cycle progression through G(1) is c-Myc dependent and independent of p27 suppression, Cdk2 activation, or E2F1-dependent transcription.
Scatter factor/hepatocyte growth factor stimulation of glioblastoma cell cycle progression through G(1) is c-Myc dependent and independent of p27 suppression, Cdk2 activation, or E2F1-dependent transcription.
复制标题
分散因子/肝细胞生长因子通过 G(1) 对胶质母细胞瘤细胞周期进展的刺激是 c-Myc 依赖性的，并且独立于 p27 抑制、Cdk2 激活或 E2F1 依赖性转录。
DOI：
10.1128/mcb.22.8.2703-2715.2002
复制
发表时间：
2002
影响因子：
5.3
通讯作者：
Laterra,John
中科院分区：
文献类型：
--
作者：
Walter,KevinA;Hossain,MirAhamed;Luddy,Carey;Goel,Nidhi;Reznik,ThomasE;Laterra,John
分散因子/肝细胞生长因子（SF/HGF）的表达与神经胶质肿瘤的恶性进展有关。通过使用两种胶质瘤细胞系U373MG和SNB-19，我们证明了SF/HGF刺激可以使细胞逃避接触抑制或血清戒断引起的G1/G0arrest。SF/HGF诱导细胞周期调控的两种机制：抑制周期蛋白依赖性激酶抑制剂p27和诱导转录因子c-Myc。SF/HGF对p27的调控是翻译后的，与p27核输出有关。瞬时转染U373MG和SNB-19野生型p27和抗降解p27T187A突变体不足以诱导细胞周期阻滞，p27的SF/HGF下调对于细胞周期重新进入不是必需的。在外源性野生型p27或p27T187A存在的情况下，对Cdk2激酶活性和p27与细胞周期蛋白E复合物结合的分析表明，Cdk2活性对于SF/ hgf介导的G1/S过渡不是必需的。同样，Cdk2的显性阴性形式的过表达不会阻止SF/ hgf触发的细胞周期进程。相反，SF/HGF通过转录上调c-Myc，并且在SF/HGF缺失的情况下，c-Myc的过表达能够阻止G1/G0arrest。MadMyc是c-Myc的显性阴性嵌合体，其短暂过表达可导致对数生长细胞的G1/ g0阻滞，并阻断SF/ hgf介导的G1/S转变。c-Myc不通过p27下调在这些细胞系中发挥作用。SF/HGF诱导e2f1依赖性转录，抑制e2f1不阻断SF/HGF诱导的细胞周期进程。我们得出结论，SF/HGF通过独立于p27、Cdk2或E2F1的c-myc依赖性机制阻止胶质瘤细胞系中的G1/ g0阻滞。
Scatter factor/hepatocyte growth factor (SF/HGF) expression has been linked to malignant progression in glial neoplasms. Using two glioma cell lines, U373MG and SNB-19, we have demonstrated that SF/HGF stimulation allows cells to escape G1/G0arrest induced by contact inhibition or serum withdrawal. SF/HGF induced effects on two mechanisms of cell cycle regulation: suppression of the cyclin-dependent kinase inhibitor p27 and induction of the transcription factor c-Myc. Regulation of p27 by SF/HGF was posttranslational and is associated with p27 nuclear export. Transient transfections of U373MG and SNB-19 with wild-type p27 and a degradation-resistant p27T187A mutant were insufficient to induce cell cycle arrest, and SF/HGF downregulation of p27 was not necessary for cell cycle reentry. Analysis of Cdk2 kinase activity and p27 binding to cyclin E complexes in the presence of exogenous wild-type p27 or p27T187A demonstrated that Cdk2 activity was not necessary for SF/HGF-mediated G1/S transition. Similarly, overexpression of dominant-negative forms of Cdk2 did not block SF/HGF-triggered cell cycle progression. In contrast, SF/HGF transcriptionally upregulated c-Myc, and overexpression of c-Myc was able to prevent G1/G0arrest in the absence of SF/HGF. Transient overexpression of MadMyc, a dominant-negative chimera for c-Myc, caused G1/G0arrest in logarithmically growing cells and blocked SF/HGF-mediated G1/S transition. c-Myc did not exert its effects through p27 downregulation in these cell lines. SF/HGF induced E2F1-dependent transcription, the inhibition of which did not block SF/HGF-induced cell cycle progression. We conclude that SF/HGF prevents G1/G0arrest in glioma cell lines by a c-myc-dependent mechanism that is independent of p27, Cdk2, or E2F1.