Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response
Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response
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DOI：
10.1016/s0022-2836(02)00234-6
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发表时间：
2002-05-17
影响因子：
5.6
通讯作者：
Hendershot, LM
中科院分区：
文献类型：
--
作者：
Ma, YJ;Brewer, JW;Hendershot, LM
CHOP是一种非ER定位的转录因子，其由包括ER应激在内的多种不利生理条件诱导。ER中未折叠蛋白的积累激活靶向ER驻留分子伴侣（例如BiP）和CHOP的未折叠蛋白应答途径。因此，目前尚不清楚ER应激期间的CHOP诱导是通过CHOP和ER伴侣启动子中保守的ER应激反应元件发生的，还是通过不同CHOP诱导细胞应激条件中保守的单独调节途径发生的。我们在仓鼠CHOP启动子中鉴定了一个真正的ER应激元件，并发现含有NF-Y的类似转录复合物与CHOP和BiP ER应激反应元件结合。此外，我们首次证明了C/EBP-ATF复合位点在ER应激期间对CHOP调节的重要性。ER跨膜eIF 2 α激酶PERK的激活诱导ATF 4蛋白表达，直接结合CHOP启动子中的复合位点，并因此诱导CHOP蛋白。我们认为，这种eIF 2 α-激酶/ATF 4/C/EBP-ATF复合位点途径在包括ER应激在内的各种细胞应激条件下对于CHOP调节是保守的。我们的数据表明，ERSE和PERK-ATF 4途径收敛于CHOP启动子在ER应激和提供洞察CHOP和ER伴侣蛋白表达之间的相似性和差异在正常和应激条件下。(C)2002爱思唯尔科技有限公司版权所有。
CHOP is a non-ER localized transcription factor that is induced by a variety of adverse physiological conditions including ER stress. Accumulation of unfolded proteins in the ER activates an unfolded protein response pathway that targets both ER resident chaperones (e.g. BiP) and CHOP. Hence, it is unclear if CHOP induction during ER stress occurs through the ER stress response element that is conserved in both CHOP and ER chaperone promoters, or through a separate regulatory pathway conserved among different CHOP inducing cellular stress conditions. We identified a bona fide ER stress element in the hamster CHOP promoter and found that similar transcription complexes containing NF-Y bound to both the CHOP and BiP ER stress response elements. In addition, we demonstrated for the first time the importance of the C/EBP-ATF composite site for CHOP regulation during ER stress. Activation of the ER transmembrane eIF2alpha kinase, PERK, induced ATF4 protein expression, direct binding to the composite site in CHOP promoter, and as a consequence, CHOP protein induction. We propose that this eIF2alpha-kinase/ATF4/C/EBP-ATF composite site pathway is conserved for CHOP regulation during various cellular stress conditions including ER stress. Our data indicate that both the ERSE and the PERK-ATF4 pathways converge on the CHOP promoter during ER stress and provide insights into the similarities and differences between CHOP and ER chaperone expression during normal and stress conditions. (C) 2002 Elsevier Science Ltd. All rights reserved.