CDCA4 is an E2F transcription factor family-induced nuclear factor that regulates E2F-dependent transcriptional activation and cell proliferation
CDCA4 is an E2F transcription factor family-induced nuclear factor that regulates E2F-dependent transcriptional activation and cell proliferation
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DOI：
10.1074/jbc.m603800200
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发表时间：
2006-11-24
影响因子：
4.8
通讯作者：
Yoshida, Kenichi
中科院分区：
文献类型：
--
作者：
Hayashi, Reiko;Goto, Yuya;Yoshida, Kenichi
TRIP-Br 1/p34（SEI-1）家族蛋白通过共激活E2 F1或p53依赖性转录激活来参与细胞周期进程。在这里，我们报告的鉴定人CDCA 4（也称为SEI-3/Hepp）作为一个新的靶基因的转录因子E2 F和E2 F依赖的转录激活的阻遏物。对CDCA 4启动子构建体的分析表明，在转录起始位点附近的E2 F响应序列是E2 F1 -4诱导的CDCA 4基因转录激活所必需的。染色质免疫沉淀分析表明，E2 F1和E2 F4结合到人CDCA 4基因的E2 F响应序列。与TRIP-Br 1/p34 SEI-1和TRIP-Br 2（SEI-2）一样，CDCA 4的反式激活结构域定位在C末端酸性区域175-241内。CDCA 4蛋白的反式激活功能被E2 F1 -4和DP 2抑制，但不被E2 F5 -8抑制。E2 F1对CDCA 4反式激活活性的抑制部分干扰了视网膜母细胞瘤蛋白的过表达。相反，CDCA 4抑制E2 F1 -3诱导的报告活性。CDCA 4（但不是酸性区域缺失的CDCA 4）抑制E2 F1调节的基因启动子活性。这些发现表明CDCA 4蛋白在E2 F应答启动子处起抑制剂的作用。小干扰RNA介导的癌细胞中CDCA 4表达的敲低导致细胞生长速率和DNA合成的上调。在几种人类细胞中检测到CDCA 4蛋白，并在细胞进入细胞周期的G（1）/S期时被诱导。总之，我们的研究结果表明，CDCA 4参与细胞增殖的调节，主要是通过E2 F/视网膜母细胞瘤蛋白途径。
The TRIP-Br1/p34(SEI-1) family proteins participate in cell cycle progression by coactivating E2F1- or p53-dependent transcriptional activation. Here, we report the identification of human CDCA4 ( also know as SEI-3/Hepp) as a novel target gene of transcription factor E2F and as a repressor of E2F-dependent transcriptional activation. Analysis of CDCA4 promoter constructs showed that an E2F-responsive sequence in the vicinity of the transcription initiation site is necessary for the E2F1-4 induced activation of CDCA4 gene transcription. Chromatin immunoprecipitation analysis demonstrated that E2F1 and E2F4 bound to an E2F-responsive sequence of the human CDCA4 gene. Like TRIP-Br1/p34SEI-1 and TRIP-Br2 (SEI-2), the transactivation domain of CDCA4 was mapped within C-terminal acidic region 175-241. The transactivation function of the CDCA4 protein was inhibited by E2F1-4 and DP2, but not by E2F5-8. Inhibition of CDCA4 transactivation activity by E2F1 partially interfered with retinoblastoma protein overexpression. Conversely, CDCA4 suppressed E2F1-3-induced reporter activity. CDCA4 ( but not acidic region-deleted CDCA4) suppressed E2F1- regulated gene promoter activity. These findings suggest that the CDCA4 protein functions as a suppressor at the E2F-responsive promoter. Small interfering RNA-mediated knockdown of CDCA4 expression in cancer cells resulted in up-regulation of cell growth rates and DNA synthesis. The CDCA4 protein was detected in several human cells and was induced as cells entered the G(1)/S phase of the cell cycle. Taken together, our results suggest that CDCA4 participates in the regulation of cell proliferation, mainly through the E2F/retinoblastoma protein pathway.