Laboratory of Developmental Genetics, Shandong Agricultural University, Tai'an, Shandong, 271018, China.
Department of Developmental Genetics, National Institute of Genetics, Mishima, Shizuoka, 411-8540, Japan.
Sci Rep. 2017 Sep 29;7(1):12470. doi: 10.1038/s41598-017-12766-w.
Hedgehog (Hh) signaling pathway and Cyclin E are key players in cell proliferation and organ development. Hyperactivation of hh and cyclin E has been linked to several types of cancer. However, coordination of the expression of hh and cyclin E was not well understood. Here we show that an evolutionarily conserved transcription factor Apontic (Apt) directly activates hh and cyclin E through its binding site in the promoter regions of hh and cyclin E. This Apt-dependent proper expression of hh and cyclin E is required for cell proliferation and development of the Drosophila wing. Furthermore, Fibrinogen silencer-binding protein (FSBP), a mammalian homolog of Apt, also positively regulates Sonic hh (Shh), Desert hh (Dhh), Cyclin E1 (CCNE1) and Cyclin E2 (CCNE2) in cultured human cells, suggesting evolutionary conservation of the mechanism. Apt-mediated expression of hh and cyclin E can direct proliferation of Hh-expressing cells and simultaneous growth, patterning and differentiation of Hh-recipient cells. The discovery of the simultaneous expression of Hh and principal cell-cycle regulator Cyclin E by Apt implicates insight into the mechanism by which deregulated hh and cyclin E promotes tumor formation.
刺猬（Hh）信号通路和细胞周期蛋白 E 是细胞增殖和器官发育的关键因素。Hh 和细胞周期蛋白 E 的过度激活与几种类型的癌症有关。然而，Hh 和细胞周期蛋白 E 的表达协调尚不清楚。在这里，我们表明，一个进化上保守的转录因子 Apontic（Apt）通过其在 hh 和细胞周期蛋白 E 启动子区域的结合位点，直接激活 hh 和细胞周期蛋白 E。这种 Apt 依赖性的 hh 和细胞周期蛋白 E 的适当表达对于果蝇翅膀的细胞增殖和发育是必需的。此外，纤维蛋白原沉默结合蛋白（FSBP），Apt 的哺乳动物同源物，也在培养的人类细胞中正向调节 Sonic hh（Shh）、Desert hh（Dhh）、细胞周期蛋白 E1（CCNE1）和细胞周期蛋白 E2（CCNE2），表明该机制具有进化上的保守性。Apt 介导的 hh 和细胞周期蛋白 E 的表达可以指导 Hh 表达细胞的增殖，以及 Hh 受体细胞的同时生长、模式形成和分化。Apt 同时表达 Hh 和主要细胞周期调节因子细胞周期蛋白 E 的发现，暗示了 Hh 和细胞周期蛋白 E 失调促进肿瘤形成的机制。
