A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity.
A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity.
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LIM 蛋白中的特征基序介导与检查点蛋白的结合并增加肿瘤放射敏感性
DOI：
10.1038/ncomms14059
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发表时间：
2017-01-17
影响因子：
16.6
通讯作者：
Ye Q
中科院分区：
文献类型：
--
作者：
Xu X;Fan Z;Liang C;Li L;Wang L;Liang Y;Wu J;Chang S;Yan Z;Lv Z;Fu J;Liu Y;Jin S;Wang T;Hong T;Dong Y;Ding L;Cheng L;Liu R;Fu S;Jiao S;Ye Q
肿瘤放疗抵抗涉及细胞周期途径。CDC 25磷酸酶是细胞周期的关键调节因子。然而，CDC 25的活性是如何精确控制的，在很大程度上仍然未知。在这里，我们表明，LIM结构域的蛋白质，如FHL 1，增加抑制性CDC 25磷酸化通过形成一个与CHK 2和CDC 25的复合物，并螯合在细胞质中的CDC 25通过形成另一个复合物与14-3-3和CDC 25，导致在癌细胞中的放射抗性增加。FHL 1的表达，诱导电离辐射在SP1和MLL 1依赖的方式，与癌症患者的放射抗性呈正相关。我们鉴定了LIM结构域（埃利姆）内的细胞穿透11个氨基酸基序，其足以结合CHK 2和CDC 25，减少CHK 2-CDC 25和CDC 25 -14-3-3相互作用，并增强CDC 25活性和癌症放射敏感性，伴随有丝分裂灾难和凋亡。我们的研究结果提供了新的见解，CDC 25活性调节的分子机制。LIM蛋白抑制或使用埃利姆可能是改善肿瘤放射敏感性的新策略。CDC 25磷酸酶是重要的细胞周期调节因子。在这里，作者表明，含有LIM结构域的蛋白质（例如FHL 1）诱导抑制性CDC 25磷酸化，导致辐射抗性，并且特定肽可以通过增加CDC 25活性来增加肿瘤的辐射敏感性。
Tumour radiotherapy resistance involves the cell cycle pathway. CDC25 phosphatases are key cell cycle regulators. However, how CDC25 activity is precisely controlled remains largely unknown. Here, we show that LIM domain-containing proteins, such as FHL1, increase inhibitory CDC25 phosphorylation by forming a complex with CHK2 and CDC25, and sequester CDC25 in the cytoplasm by forming another complex with 14-3-3 and CDC25, resulting in increased radioresistance in cancer cells. FHL1 expression, induced by ionizing irradiation in a SP1- and MLL1-dependent manner, positively correlates with radioresistance in cancer patients. We identify a cell-penetrating 11 amino-acid motif within LIM domains (eLIM) that is sufficient for binding CHK2 and CDC25, reducing the CHK2–CDC25 and CDC25–14-3-3 interaction and enhancing CDC25 activity and cancer radiosensitivity accompanied by mitotic catastrophe and apoptosis. Our results provide novel insight into molecular mechanisms underlying CDC25 activity regulation. LIM protein inhibition or use of eLIM may be new strategies for improving tumour radiosensitivity. CDC25 phosphatases are important cell cycle regulators. Here, the authors show that the LIM domain-containing proteins (for example, FHL1) induce inhibitory CDC25 phosphorylation resulting in radioresistance and that a specific peptide can increase tumour radiosensitivity by increasing CDC25 activity.