Gene expression of transcriptional repressor ATF3 and its biological role

应激反应是机体对外界刺激的一种适应机制，在决定细胞增殖或死亡等命运中起着至关重要的作用。因此，即时早期反应基因（IEG）被认为是控制下游通路响应外部压力的基因组守门人。激活转录因子（ATF） 3是碱性亮氨酸拉链（b-Zip）型转录因子ATF/CREB家族的成员。其mRNA水平在大多数细胞中较低或检测不到，但受多种应激信号的诱导。这种反应对细胞命运有双重影响，如细胞周期阻滞和凋亡，或细胞存活和增殖。在本次资助期间，我们揭示了应激反应IEG， ATF3的生物学功能。1) ATF3的P1启动子在人和小鼠之间是保守的，在各种刺激下都有功能，而P1启动子主要由血清诱导，P2启动子在TGF-β和致癌HRAS的作用下更有效地被激活。在ATF3表达升高的人前列腺癌和霍奇金Reed-Sternberg癌细胞中，P1启动子被组成性激活，其染色质结构被修饰为活性构型。ATF3基因的替代启动子在转录和翻译水平上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中决定细胞命运的ATF3表达提供了一种新的机制（核酸Res 2009）。2)在紫外线照射的人角质细胞中发现了新的ATF3靶基因p15。在低剂量紫外线下，ATF3-p15通路促进DNA修复，而在高剂量紫外线下，ATF3-Hif2alpha通路诱导细胞死亡。这为应激反应基因在应激反应中控制双细胞命运提供了分子基础（cell Death and Differentiation, 2008）。3) ATF3是toll样受体4在炎症中的负调节因子。ATF3在ffa处理的巨噬细胞中的生物学意义表明，ATF3可能控制肥胖脂肪组织的炎症反应（Circulation Research 2008）。4)结合表达芯片和ChIP-chip筛选ATF3结合靶基因，对DNA损伤应答基因进行全基因组分析，发现ATF3在DNA损伤应答中是p53的激活因子，但在人类癌症如前列腺中是p53的负调节因子。5)为了进一步研究p53-ATF3轴，我们开发了ATF3空小鼠和p53/ATF3双KO小鼠。少

Stress response is an adaptation mechanism to external stimuli of organism, which plays crucial role in determining cell fate such as cell proliferation or death. Thus, immediate early response genes (IEG) sidered as genomic gatekeeper that controls downstream pathway in response to external stress. Among ~40 IEGs, Activating transcription factor (ATF) 3 is a member of the ATF/CREB family of basic-leucine zipper (b-Zip) type transcription factors. Its mRNA level is low or undetectable in most cells, but is greatly induced by a variety of stress signal. This response has dual effects on cell fate, such as cell cycle arrest and apoptosis, or cell survival and proliferation. In the period of this grant, we revealed following biological function of stress response IEG, ATF3. 1) The P1 promoter of ATF3 is 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 activat … More ed in response to TGF-β and oncogenic HRAS. 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 (Nucleic Acid Res 2009). 2) Novel target gene of ATF3 in UV-irradiated human keratinocyte, p15, was identified. At low dose of UV, ATF3-p15 pathway promotes DNA repair, but cell death pathway was induced at high dose UV via ATF3-Hif2alpha. This provides molecular basis why this stress response gene could control dual cell fate in stress response (Cell Death and Differentiation 2008). 3) ATF3 is negative regulator of Toll-like receptor4 in inflammation. Biological implication of ATF3 in FFA-treated macrophages shows that ATF3 may control inflammatory response in fatty tissue of obesity (Circulation Research 2008). 4) Using genome-wide analysis of DNA damage response genes by combination of expression microarray and ChIP-chip screening of ATF3-binding target genes, we found ATF3 functions an activator of p53 in DNA damage response, but negative regulator of p53 in human cancer such as prostate. 5) In order to further our research of p53-ATF3 axis, we developed ATF3 null mouse and p53/ATF3 double KO mouse. Less