Department of Biochemistry and Molecular Biology, Brain Korea 21 Division of Cell Transformation and Restoration, Ajou University, School of Medicine, Suwon, Korea.
Carcinogenesis. 2013 Aug;34(8):1907-17. doi: 10.1093/carcin/bgt134. Epub 2013 Apr 24.
Forkhead Box M1 (FoxM1) protein is a transcription factor and regulates cell cycle. It is commonly upregulated in human cancer tissue and correlated with poor prognosis, suggesting that the overexpression of FoxM1 plays a critical role in carcinogenesis. In this study, we report the identification and characterization of a new variant of FoxM1, which was first isolated from our laboratory in hepatoma cell lines. Compared with wild-type FoxM1, the new variant lacks of C-terminus of FoxM1 (FoxM1ΔC), which is a transactivation domain. Reverse transcription-polymerase chain reaction and western blot analysis demonstrated that FoxM1ΔC was highly expressed in a variety of cancer cell lines such as HepG2, HeLa, A549, MB231, EJ, U2OS, Hep3B and MCF7, but not expressed in normal human dermal fibroblast (HDF). Immunoprecipitation assay revealed that FoxM1ΔC interacted with wild-type FoxM1. Furthermore, FoxM1ΔC bound to FoxM1 targeted gene promoter region and correlated with dysregulation of wild-type FoxM1. FoxM1ΔC delayed G2/M to G1 progression of cell cycle, decreased Aurora B(T232) phosphorylation and increased chromosome centromere interspace. Finally, FoxM1ΔC induced instability of chromosome and formation of aneuploid cells within 1 month when expressed in HDF. In conclusion, FoxM1ΔC is expressed in cancer cells and dysregulates normal cell cycle and induces chromosome instability.
叉头框蛋白 M1（FoxM1）蛋白是一种转录因子，调节细胞周期。它在人类癌症组织中通常上调，并与预后不良相关，表明 FoxM1 的过表达在致癌作用中起关键作用。在这项研究中，我们报告了一种新的 FoxM1 变体的鉴定和特征，该变体最初是从我们实验室的肝癌细胞系中分离出来的。与野生型 FoxM1 相比，新变体缺乏 FoxM1 的 C 端（FoxM1ΔC），这是一个转录激活结构域。反转录-聚合酶链反应和 Western blot 分析表明，FoxM1ΔC 在多种癌细胞系中高度表达，如 HepG2、HeLa、A549、MB231、EJ、U2OS、Hep3B 和 MCF7，但在正常的人皮肤成纤维细胞（HDF）中不表达。免疫沉淀分析表明 FoxM1ΔC 与野生型 FoxM1 相互作用。此外，FoxM1ΔC 结合 FoxM1 靶向基因启动子区域，并与野生型 FoxM1 的失调相关。FoxM1ΔC 延迟细胞周期从 G2/M 到 G1 的进展，降低 Aurora B（T232）磷酸化并增加染色体着丝粒间隔。最后，FoxM1ΔC 在 HDF 中表达时，在 1 个月内诱导染色体不稳定和非整倍体细胞的形成。总之，FoxM1ΔC 在癌细胞中表达，失调正常细胞周期并诱导染色体不稳定。
