FBXO31 protects against genomic instability by capping FOXM1 levels at the G2/M transition
FBXO31 protects against genomic instability by capping FOXM1 levels at the G2/M transition
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DOI：
10.1038/onc.2016.268
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发表时间：
2017-02-16
期刊：
影响因子：
8
通讯作者：
Khanna, K. K.
中科院分区：
文献类型：
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作者：
Jeffery, J. M.;Kalimutho, M.;Khanna, K. K.
F-box蛋白与Skp1， Cul1和Rbx1结合产生SCF复合物，该复合物负责蛋白质的泛素化，导致其活化或降解。在这里，我们发现F-box蛋白FBXO31是正常有丝分裂进程和基因组稳定所必需的，因为它在G2/M过渡期间调节FOXM1水平。fbxo31缺失的细胞经历短暂的有丝分裂延迟，这是由于激活纺锤体检查点伴随着滞后染色体和后期桥的增加。FBXO31部分通过控制FOXM1的水平来调节有丝分裂，FOXM1是一种转录因子和有丝分裂的主要调节因子。FBXO31在G2/M转变过程中特异性地与FOXM1相互作用，导致FOXM1泛素化和降解。FBXO31缺失导致FOXM1转录靶点表达增加，并模仿FOXM1过表达。相比之下，FBXO31和FOXM1的共缺失恢复了基因组不稳定表型，但没有延迟有丝分裂，这表明FBXO31可能有额外的有丝分裂底物。因此，FBXO31是第一个在G2/M转变过程中被描述的FOXM1负调控因子。
F-box proteins in conjunction with Skp1, Cul1 and Rbx1 generate SCF complexes that are responsible for the ubiquitination of proteins, leading to their activation or degradation. Here we show that the F-box protein FBXO31 is required for normal mitotic progression and genome stability due to its role in regulating FOXM1 levels during the G2/M transition. FBXO31-depleted cells undergo a transient delay in mitosis due to an activated spindle checkpoint concomitant with an increase in lagging chromosomes and anaphase bridges. FBXO31 regulates mitosis in part by controlling the levels of FOXM1, a transcription factor and master regulator of mitosis. FBXO31 specifically interacts with FOXM1 during the G2/M transition, resulting in FOXM1 ubiquitination and degradation. FBXO31 depletion results in increased expression of FOXM1 transcriptional targets and mimics the FOXM1 overexpression. In contrast, co-depletion of FBXO31 and FOXM1 restores the genomic instability phenotype but not the delay in mitosis, indicating that FBXO31 probably has additional mitotic substrates. Thus, FBXO31 is the first described negative regulator of FOXM1 during the G2/M transition.