Nicolás Francisco J, Hill Caroline S
Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, UK.
Oncogene. 2003 Jun 12;22(24):3698-711. doi: 10.1038/sj.onc.1206420.
We have investigated the mechanism whereby tumor cells become resistant to the antiproliferative effects of transforming growth factor (TGF)-beta, while maintaining other responses that can lead to increased malignancy and invasiveness. TGF-beta signaling results in nuclear accumulation of active Smad complexes which regulate transcription of target genes. Here we show that in two pancreatic carcinoma cell lines, PT45 and Panc-1, that are resistant to TGF-beta-induced growth arrest, the TGF-beta-Smad signaling pathway is attenuated compared with epithelial cells that are sensitive to the antiproliferative effects of TGF-beta (HaCaT and Colo-357). In PT45 and Panc-1 cells, active Smad complexes remain nuclear for only 1-2 h compared with more than 6 h in HaCaT and Colo-357 cells. The attenuated pathway in PT45 and Panc-1 cells correlates with low levels of TGF-beta type I receptor and results in an altered expression profile of TGF-beta-inducible genes required for cell cycle arrest. Most significantly, expression of the CDK inhibitor, p21(Cip1/WAF1), which is required for TGF-beta-induced growth arrest in these cells, is not maintained. Moreover, we show that artificially attenuating the TGF-beta-Smad signaling pathway in HaCaT cells is sufficient to prevent TGF-beta-induced growth arrest. Our results demonstrate that the duration of TGF-beta-Smad signaling is a critical determinant of the specificity of the TGF-beta response.
我们研究了肿瘤细胞对转化生长因子（TGF）-β的抗增殖作用产生抗性的机制，同时这些肿瘤细胞还维持着其他可导致恶性程度增加和侵袭性增强的反应。TGF-β信号传导导致活性Smad复合物在细胞核内积累，从而调节靶基因的转录。在此我们表明，在对TGF-β诱导的生长停滞具有抗性的两种胰腺癌细胞系PT45和Panc-1中，与对TGF-β的抗增殖作用敏感的上皮细胞（HaCaT和Colo-357）相比，TGF-β-Smad信号通路减弱。在PT45和Panc-1细胞中，活性Smad复合物在细胞核内仅保留1-2小时，而在HaCaT和Colo-357细胞中则超过6小时。PT45和Panc-1细胞中减弱的信号通路与低水平的TGF-βI型受体相关，并导致细胞周期停滞所需的TGF-β诱导基因的表达谱发生改变。最显著的是，这些细胞中TGF-β诱导生长停滞所需的细胞周期蛋白依赖性激酶抑制剂p21（Cip1/WAF1）的表达未能维持。此外，我们表明在HaCaT细胞中人为减弱TGF-β-Smad信号通路足以阻止TGF-β诱导的生长停滞。我们的结果表明，TGF-β-Smad信号传导的持续时间是TGF-β反应特异性的关键决定因素。
