Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus
Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus
复制标题
DOI：
10.1073/pnas.231467698
复制
发表时间：
2001-12-18
影响因子：
11.1
通讯作者：
Tsichlis, PN
中科院分区：
文献类型：
--
作者：
Malstrom, S;Tili, E;Tsichlis, PN
表达近端Lck启动子构建的MyrAkt的转基因小鼠在幼年时发展为胸腺瘤，而表达构成型活性Lck- akte40k的转基因小鼠在晚年主要发展为外周淋巴器官肿瘤。6- 8周龄MyrAkt转基因小鼠胸腺大小正常，但比非转基因对照和AktE40K转基因小鼠胸腺含有更少、更大的细胞。早期的研究表明，细胞大小和细胞周期是协调调节的。基于这一发现，以及我们观察到Akt的致癌潜能与其对细胞大小的影响相关，我们假设旨在维持胸腺大小的机制通过阻断myrakt促进的G(1)进展来解离细胞大小和细胞周期调节，这些机制的失败可能促进细胞增殖，导致肿瘤胸腺增大。为了验证这一假设，我们检测了转基因和非转基因对照小鼠新鲜分离和培养的胸腺细胞的细胞周期分布。结果表明，虽然转基因没有改变原位细胞周期分布，但MyrAkt转基因促进了培养中G(1)的进展。新分离的MyrAkt胸腺细胞表达高水平的细胞周期蛋白D2、E和cdk4，但低于正常水平的细胞周期蛋白D3和cdk2。另一方面，MyrAkt转基因小鼠培养的胸腺细胞表达高水平的cyclin D3，这表明假设的器官大小控制机制可能下调该分子的表达。原发肿瘤细胞，类似于培养的MyrAkt胸腺细胞，表达高水平的细胞周期蛋白D3。这些发现支持了肿瘤诱导是由器官大小控制机制下调cyclin D3和阻止myrakt促进的G(1)进展失败引起的假设。
Transgenic mice expressing MyrAkt from a proximal Lck promoter construct develop thymomas at an early age, whereas transgenic mice expressing constitutively active Lck-AktE40K develop primarily tumors of the peripheral lymphoid organs later in life. The thymus of 6- to 8-week-old MyrAkt transgenic mice is normal in size but contains fewer, larger cells than the thymus of nontransgenic control and AktE40K transgenic mice. Earlier studies had shown that cell size and cell cycle are coordinately regulated. On the basis of this finding, and our observations that the oncogenic potential of Akt correlates with its effect on cell size, we hypothesized that mechanisms aimed at maintaining the size of the thymus dissociate cell size and cell cycle regulation by blocking MyrAkt-promoted G(1) progression and that failure of these mechanisms may promote cell proliferation resulting in an enlarged neoplastic thymus. To address this hypothesis, we examined the cell cycle distribution of freshly isolated and cultured thymocytes from transgenic and nontransgenic control mice. The results showed that although neither transgene alters cell cycle distribution in situ, the MyrAkt transgene promotes G(1) progression in culture. Freshly isolated MyrAkt thymocytes express high levels of cyclins D2 and E and cdk4 but lower than normal levels of cyclin D3 and cdk2. Cultured thymocytes from MyrAkt transgenic mice, on the other hand, express high levels of cyclin D3, suggesting that the hypothesized organ size control mechanisms may down-regulate the expression of this molecule. Primary tumor cells, similar to MyrAkt thymocytes in culture, express high levels of cyclin D3. These findings support the hypothesis that tumor induction is caused by the failure of organ size control mechanisms to downregulate cyclin D3 and to block MyrAkt-promoted G(1) progression.