CHOP Enhancement of Gene Transcription by Interactions with Jun/Fos AP-1 Complex Proteins
CHOP Enhancement of Gene Transcription by Interactions with Jun/Fos AP-1 Complex Proteins
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DOI：
10.1128/mcb.19.11.7589
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发表时间：
1999-11
影响因子：
5.3
通讯作者：
M. Ubeda;M. Vallejo;J. Habener
中科院分区：
文献类型：
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作者：
M. Ubeda;M. Vallejo;J. Habener
摘要 转录因子 CHOP（C/EBP 同源蛋白 10）是一种 bZIP 蛋白，由多种刺激诱导，可引起细胞应激反应，并已被证明可以阻止细胞生长并促进程序性细胞死亡。 CHOP 不能形成同二聚体，但可以与激活转录因子的 C/EBP 家族形成稳定的异二聚体。尽管最初被定性为基因转录激活中 C/EBP 的显性失活抑制剂，但 CHOP-C/EBP 可以激活某些靶基因。在这里，我们展示了 CHOP 与立即早期反应、生长促进 AP-1 转录因子家族 JunD、c-Jun 和 c-Fos 的成员相互作用，以激活生长抑素、JunD 和胶原酶基因中的启动子元件。亮氨酸拉链二聚化结构域是与 AP-1 蛋白相互作用和转录反式激活所必需的。通过电泳迁移率变动分析和体内哺乳动物双杂交系统进行的蛋白质-蛋白质相互作用分析表明，CHOP 与细胞内的 AP-1 蛋白质相互作用，并表明它通过束缚机制而不是通过直接结合 DNA 被招募到 AP-1 复合物中。因此，CHOP 不仅是 C/EBP 靶基因的负调节或正调节，而且当与 AP-1 因子结合时，可以激活 AP-1 靶基因。这些发现证实了一种新机制的存在，当细胞暴露于细胞应激时，CHOP 通过该机制调节基因表达。
ABSTRACT The transcription factor CHOP (C/EBP homologous protein 10) is a bZIP protein induced by a variety of stimuli that evoke cellular stress responses and has been shown to arrest cell growth and to promote programmed cell death. CHOP cannot form homodimers but forms stable heterodimers with the C/EBP family of activating transcription factors. Although initially characterized as a dominant negative inhibitor of C/EBPs in the activation of gene transcription, CHOP-C/EBP can activate certain target genes. Here we show that CHOP interacts with members of the immediate-early response, growth-promoting AP-1 transcription factor family, JunD, c-Jun, and c-Fos, to activate promoter elements in the somatostatin, JunD, and collagenase genes. The leucine zipper dimerization domain is required for interactions with AP-1 proteins and transactivation of transcription. Analyses by electrophoretic mobility shift assays and by an in vivo mammalian two-hybrid system for protein-protein interactions indicate that CHOP interacts with AP-1 proteins inside cells and suggest that it is recruited to the AP-1 complex by a tethering mechanism rather than by direct binding of DNA. Thus, CHOP not only is a negative or a positive regulator of C/EBP target genes but also, when tethered to AP-1 factors, can activate AP-1 target genes. These findings establish the existence of a new mechanism by which CHOP regulates gene expression when cells are exposed to cellular stress.