Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Mol Biol Cell. 2012 Aug;23(15):2856-66. doi: 10.1091/mbc.E10-12-1010. Epub 2012 Jun 13.
Our previous data suggested that the human basic helix-loop-helix transcription factor achaete-scute homologue-1 (hASH1) may stimulate both proliferation and migration in the lung. In the CNS, cyclin-dependent kinase 5 (Cdk5) and its activator p35 are important for neuronal migration that is regulated by basic helix-loop-helix transcription factors. Cdk5/p35 may also play a role in carcinogenesis. In this study, we found that the neuronal activator p35 was commonly expressed in primary human lung cancers. Cdk5 and p35 were also expressed by several human lung cancer cell lines and coupled with migration and invasion. When the kinase activity was inhibited by the Cdk5 inhibitor roscovitine or dominant-negative (dn) Cdk5, the migration of lung cancer cells was reduced. In neuroendocrine cells expressing hASH1, such as a pulmonary carcinoid cell line, knocking down the gene expression by short hairpin RNA reduced the levels of Cdk5/p35, nuclear p35 protein, and migration. Furthermore, expression of hASH1 in lung adenocarcinoma cells normally lacking hASH1 increased p35/Cdk5 activity and enhanced cellular migration. We were also able to show that p35 was a direct target for hASH1. In conclusion, induction of Cdk5 activity is a novel mechanism through which hASH1 may regulate migration in lung carcinogenesis.
我们之前的数据表明，人类基本螺旋-环-螺旋转录因子achaete-scute 同源物-1（hASH1）可能刺激肺中的增殖和迁移。在中枢神经系统中，细胞周期蛋白依赖性激酶 5（Cdk5）及其激活剂 p35 对于受基本螺旋-环-螺旋转录因子调节的神经元迁移很重要。Cdk5/p35 也可能在致癌作用中发挥作用。在这项研究中，我们发现神经元激活剂 p35在原发性人肺癌中普遍表达。几种人肺癌细胞系也表达 Cdk5 和 p35，并与迁移和侵袭相关。当激酶活性被 Cdk5 抑制剂 roscovitine 或显性负（dn）Cdk5 抑制时，肺癌细胞的迁移减少。在表达 hASH1 的神经内分泌细胞中，如肺类癌细胞系，通过短发夹 RNA 敲低基因表达会降低 Cdk5/p35、核 p35 蛋白和迁移水平。此外，在通常缺乏 hASH1 的肺腺癌细胞中表达 hASH1 会增加 p35/Cdk5 活性并增强细胞迁移。我们还能够表明 p35 是 hASH1 的直接靶标。总之，诱导 Cdk5 活性是 hASH1 可能调节肺癌发生中迁移的新机制。
