Miyazaki Keisuke, Inoue Shoko, Yamada Kazuhiko, Watanabe Masashi, Liu Qin, Watanabe Toshiki, Adachi Mimi Tamamori, Tanaka Yujiro, Kitajima Shigetaka
Department of Biochemical Genetics, Medical Research Institute and Laboratory of Genome Structure and Regulation, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Nucleic Acids Res. 2009 Apr;37(5):1438-51. doi: 10.1093/nar/gkn1082. Epub 2009 Jan 9.
Stress response gene ATF3 plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli. An alternate promoter of the human ATF3 gene (designated P1 in this study) has recently been reported, which is located approximately 43.5 kb upstream of the previously reported P2 promoter. We showed here that the P1 promoter is highly conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activated in response to TGF-beta and oncogenic HRAS. The P1 promoter contains multiple transcriptional start sites, and the different 5'-UTRs markedly affected their translation in response to stress. In human prostate and Hodgkin Reed-Sternberg cancer cells with elevated expression of ATF3, the P1 promoter was constitutively activated and its chromatin structure was modified into active configuration. The differential usage of alternate promoters of the ATF3 gene at both transcriptional and translational level and the modification of chromatin structure may provide a novel mechanism for expressing ATF3 in determining cell fate during stress response and cancer.
应激反应基因ATF3在响应有丝分裂原或应激刺激时决定细胞命运方面发挥多效性作用。最近报道了人类ATF3基因的一个替代启动子（本研究中命名为P1），它位于先前报道的P2启动子上游约43.5 kb处。我们在此表明，P1启动子在人和小鼠之间高度保守，并且对各种刺激有功能响应，而P1启动子主要由血清诱导，P2启动子在响应TGF-β和致癌性HRAS时更有效地被激活。P1启动子包含多个转录起始位点，不同的5'-UTR在应激反应中显著影响它们的翻译。在ATF3表达升高的人前列腺癌细胞和霍奇金-里德-斯腾伯格癌细胞中，P1启动子被组成性激活，其染色质结构被修饰成活性构型。ATF3基因替代启动子在转录和翻译水平的差异使用以及染色质结构的修饰可能为应激反应和癌症期间ATF3在决定细胞命运中的表达提供一种新机制。
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