Proteasome-dependent Degradation of Transcription Factor Activating Enhancer-binding Protein 4 (TFAP4) Controls Mitotic Division
Proteasome-dependent Degradation of Transcription Factor Activating Enhancer-binding Protein 4 (TFAP4) Controls Mitotic Division
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DOI：
10.1074/jbc.m114.549535
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发表时间：
2014-03-14
影响因子：
4.8
通讯作者：
Guardavaccaro, Daniele
中科院分区：
文献类型：
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作者：
D'Annibale, Sara;Kim, Jihoon;Guardavaccaro, Daniele
工作背景：TFAP 4是控制细胞增殖、干性和上皮-间质转化的转录因子，并且在结直肠癌中上调。结果：TFAP 4被SCFTrCP泛素连接酶靶向降解。不能降解TFAP 4导致异常有丝分裂。结论：TFAP 4的降解是有丝分裂保真度所必需的。重要性：TFAP 4是一种基本的螺旋-环-螺旋转录因子，调节细胞增殖、干细胞和上皮-间质转化等多种基因的表达，在结直肠癌和其他一些人类恶性肿瘤中表达上调。我们发现，在细胞分裂周期的G（2）期，TFAP 4被SCFTrCP泛素连接酶靶向蛋白酶体依赖性降解。该事件需要TFAP 4在保守的降解决定子上的磷酸化。不能与TrCP相互作用的稳定TFAP 4突变体的表达导致许多有丝分裂缺陷，包括染色体错误分离和多极纺锤体，其最终导致DNA损伤反应的激活。我们的研究结果表明，有丝分裂的保真度需要TFAP 4的TrCP依赖性降解。
Background: TFAP4 is a transcription factor that controls cell proliferation, stemness and epithelial-mesenchymal transition and is up-regulated in colorectal cancer. Results: TFAP4 is targeted for degradation by the SCFTrCP ubiquitin ligase. Failure to degrade TFAP4 leads to aberrant mitosis. Conclusion: TFAP4 degradation is required for the fidelity of mitosis. Significance: Misregulation of TFAP4 might contribute to genomic instability and tumorigenesis.TFAP4, a basic helix-loop-helix transcription factor that regulates the expression of a multitude of genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition, is up-regulated in colorectal cancer and a number of other human malignancies. We have found that, during the G(2) phase of the cell division cycle, TFAP4 is targeted for proteasome-dependent degradation by the SCFTrCP ubiquitin ligase. This event requires phosphorylation of TFAP4 on a conserved degron. Expression of a stable TFAP4 mutant unable to interact with TrCP results in a number of mitotic defects, including chromosome missegregation and multipolar spindles, which eventually lead to the activation of the DNA damage response. Our findings reveal that TrCP-dependent degradation of TFAP4 is required for the fidelity of mitotic division.