Gene expression of transcriptional repressor ATF3 and its biological role

转录抑制因子ATF3的基因表达及其生物学作用

基本信息

批准号：
21590302
负责人：
KITAJIMA Shigetaka
金额：
$ 3.08万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

项目摘要

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

应激反应是生物体对外部刺激的适应机制，在细胞增殖或死亡等细胞命运中起着至关重要的作用，因此，立即早期反应基因（IEG）被认为是控制下游通路以应对外部应激的基因组守门人。在约 40 个 IEG 中，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，但在大多数细胞中含量很高。这种反应对细胞命运有双重影响，如细胞周期停滞和细胞凋亡，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的以下生物学功能。 1) ATF3 的 P1 启动子在人类和小鼠之间是保守的，并且在响应各种刺激时发挥功能，而 P1 启动子主要由血清诱导，P2 启动子在响应 TGF-β 和致癌物质时更有效地被激活。 HRAS。在 ATF3 表达升高的人类前列腺癌细胞和霍奇金-里德-斯滕伯格癌细胞中，P1 启动子被组成型激活，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。染色质结构的修饰可能提供表达 ATF3 来决定应激反应和癌症期间细胞命运的新机制 (Nucleic Acid Res 2009)。在紫外线照射的人角质形成细胞中，鉴定出 ATF3 的新靶基因 p15，在低剂量紫外线下，ATF3-p15 途径促进 DNA 修复，但在高剂量紫外线下通过 ATF3-Hif2α 诱导细胞死亡途径。为什么这个应激反应基因可以控制应激反应中的双重细胞命运（细胞死亡和分化3）ATF3是炎症中Toll样受体4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 可以控制肥胖脂肪组织中的炎症反应（Circulation Research 2008），通过结合表达微阵列和 ChIP 芯片筛选对 DNA 损伤反应基因进行全基因组分析。 ATF3 结合靶基因，我们发现 ATF3 在 DNA 损伤反应中充当 p53 的激活剂，但在人类癌症（如前列腺）中充当 p53 的负调节剂 5）。为了进一步研究p53-ATF3轴，我们开发了ATF3 null小鼠和p53/ATF3双KO小鼠。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of ATF3 constitutes as a negative regulator of saturated fatty acid/Toll-like receptor 4 signaling and macrophage activation in obese adipose tissue

ATF3 的作用构成肥胖脂肪组织中饱和脂肪酸/Toll 样受体 4 信号传导和巨噬细胞激活的负调节因子

DOI：
发表时间：
2009
期刊：
Circ Res 105
影响因子：
0
作者：
Suganami T;Yuan X;Shimoda Y;Uchio-Yamada K;et al
通讯作者：
et al

ストレス応答遺伝子ATF3はCamptothecinによるDR5発現を正に制御する

应激反应基因ATF3正向调节喜树碱诱导的DR5表达

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
武谷憲二;川内潤也;田中裕二郎;前原喜彦;北嶋繁孝
通讯作者：
北嶋繁孝

Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.

DOI：
10.1093/nar/gkn1082
发表时间：
2009-04
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Miyazaki K;Inoue S;Yamada K;Watanabe M;Liu Q;Watanabe T;Adachi MT;Tanaka Y;Kitajima S
通讯作者：
Kitajima S

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV.

ATF3 和 p15PAF 是紫外线下基因组完整性的新型看门人。