SUMOylation inhibits FOXM1 activity and delays mitotic transition.
SUMOylation inhibits FOXM1 activity and delays mitotic transition.
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叉头盒转录因子FOXM 1是G2/M期转换、有丝分裂和DNA损伤反应的重要效应子。因此，它在肿瘤发生过程中经常被解除管制。在这里，我们报告说，FOXM 1是动态修改的SUMO 1，但不是SUMO 2/3在多个网站。我们发现，FOXM 1 SUMO化在MCF-7乳腺癌细胞中增强，以响应表阿霉素和有丝分裂抑制剂的治疗。突变的五个共识共轭基序产生SUMO化缺陷突变体FOXM 1。相反，E2连接酶Ubc 9与FOXM 1的融合产生了一个自动SUMO化突变体（FOXM 1-Ubc 9）。野生型FOXM 1和突变体的分析表明，SUMO化抑制FOXM 1的活性，促进易位到细胞质和增强APC/Cdh 1介导的泛素化和降解。此外，SUMO化缺陷突变体的表达与野生型FOXM 1相比增强了细胞增殖，而FOXM 1-Ubc 9融合蛋白导致细胞周期蛋白B1的持续表达，并减缓了从有丝分裂进入到退出的时间。总之，我们的研究结果表明，SUMO化减弱FOXM 1的活性，并导致细胞毒性药物反应的有丝分裂延迟。
The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response.
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