Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells
Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells
复制标题
DOI：
10.1038/sj.onc.1203470
复制
发表时间：
2000-03-23
期刊：
影响因子：
8
通讯作者：
Hynes, NE
中科院分区：
文献类型：
--
作者：
Neve, RM;Sutterlüty, H;Hynes, NE
ErbB 2受体酪氨酸激酶在多种人类肿瘤中过表达。为了了解ErbB 2介导肿瘤增殖的机制，我们使用胞内表达的ER靶向单链抗体（scFV-5 R）功能性地灭活了ErbB 2受体。在ErbB 2过表达的SKBr 3乳腺癌细胞系中，scFV-5 R的诱导表达导致质膜定位的ErbB 2的丢失，同时，ErbB 3、MAP激酶和PKB/Akt的活性显著降低，提示活性ErbB 2/ErbB 3二聚体对于这些激酶的持续活性是必需的。功能性ErbB 2的丧失导致SKBr 3肿瘤细胞在细胞周期的G1期积累，这是CDK 2活性降低的结果，这是由p27（Kip 1）从螯合复合物重新分布到细胞周期蛋白E/CDK 2复合物介导的。c-Myc和D-细胞周期蛋白的水平，参与p27（Kip 1）隔离，在功能性ErbB 2的情况下下降。c-Myc的异位表达导致D细胞周期蛋白水平和CDK 2活性的增加，并导致部分G1期挽救。我们认为c-Myc是ErbB 2介导的致癌性的主要效应子，其功能是阻止正常p27（Kip 1）对cyclinE/CDR 2的控制。
The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human tumours. In order to understand the mechanism by which ErbB2 mediates tumour proliferation we have functionally inactivated the receptor using an intracellularly expressed, ER-targeted single-chain antibody (scFV-5R), Inducible expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cell line leads to loss of plasma membrane localized ErbB2, Simultaneously, the activity of ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggesting that active ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of functional ErbB2 caused the SKBr3 tumour cells to accumulate in the G1 phase of the cell cycle, This was a result of reduction in CDK2 activity, which was mediated by a re-distribution of p27(Kip1) from sequestering complexes to cyclin E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27(Kip1) sequestration, decreased in the absence of functional ErbB2. Ectopic expression of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a partial G1 rescue. We propose that c-Myc is a primary effector of ErbB2-mediated oncogenicity and functions to prevent normal p27(Kip1) control of cyclinE/CDR2.