The epithelial cell transforming sequence 2, a guanine nucleotide exchange factor for Rho GTPases, is repressed by p53 via protein methyltransferases and is required for G1-S transition
The epithelial cell transforming sequence 2, a guanine nucleotide exchange factor for Rho GTPases, is repressed by p53 via protein methyltransferases and is required for G1-S transition
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DOI：
10.1158/0008-5472.can-06-0121
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Xinbin
中科院分区：
文献类型：
--
作者：
Scoumanne, Ariane;Chen, Xinbin
上皮细胞转化序列2（ECT 2）是Rho GTPases鸟嘌呤核苷酸交换因子Db 1家族的成员，是胞质分裂所必需的。肿瘤抑制因子p53在协调细胞过程中起着至关重要的作用，如细胞周期停滞和凋亡，以响应应激信号。在这里，我们表明，ECT 2是负调控野生型p53，但不是肿瘤衍生的突变型p53或其他p53家族成员。此外，在多种细胞系中，DNA损伤剂和NDM 2拮抗剂Nutlin-3以p53依赖性方式下调ECT 2。我们还发现，ECT 2启动子的活性受到野生型p53的抑制，在较小程度上受到p21的抑制。此外，p53中的第二激活结构域对于有效抑制ECT 2是必需的。重要的是，我们发现ECT 2基因在体内响应DNA损伤和Nutlin-3治疗时被p53结合。此外，我们提供的证据表明，抑制蛋白质甲基转移酶，特别是精氨酸甲基转移酶，解除抑制ECT 2诱导的DNA损伤或Nutlin-3的p53依赖性的方式。最后，我们产生了多个细胞系，其中，ECT 2被诱导敲低，并发现ECT 2敲低触发细胞周期停滞在G（1）。总之，我们发现了一个新的功能ECT 2，并提供了一个新的机制，p53抑制基因表达通过蛋白质甲基转移酶。
The epithelial cell transforming sequence 2 (ECT2), a member of the Db1 family of guanine nucleotide exchange factor for Rho GTPases, is required for cytokinesis. The tumor suppressor p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest and apoptosis, in response to stress signals. Here, we showed that ECT2 is negatively regulated by wild-type p53 but not tumor-derived mutant p53 or other p53 family members. In addition, ECT2 is down-regulated in multiple cell lines by DNA damage agents and Nutlin-3, an NDM2 antagonist, in a p53-dependent manner. We also showed that the activity of the ECT2 promoter is repressed by wild-type p53, and to a lesser extent, by p21. In addition, the second activation domain in p53 is necessary for the efficient repression of ECT2. Importantly, we found that the ECT2 gene is bound by p53 in vivo in response to DNA damage and Nutlin-3 treatment. Furthermore, we provided evidence that inhibition of protein methyltransferases, especially arginine methyltransferases, relieve the repression of ECT2 induced by DNA damage or Nutlin-3 in a p53-dependent manner. Finally, we generated multiple cell lines in which, ECT2 is inducibly knocked down and found that ECT2 knockdown triggers cell cycle arrest in G(1). Taken together, we uncovered a novel function for ECT2 and provided a novel mechanism by which p53 represses gene expression via protein methyltransferases.