Gcn4p and novel upstream activating sequences regulate targets of the unfolded protein response.
Gcn4p and novel upstream activating sequences regulate targets of the unfolded protein response.
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DOI：
10.1371/journal.pbio.0020246
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发表时间：
2004-08
期刊：
影响因子：
9.8
通讯作者：
Walter P
中科院分区：
文献类型：
--
作者：
Patil CK;Li H;Walter P
真核细胞通过激活未折叠蛋白反应（UPR）来响应内质网（ER）中未折叠蛋白的积累，所述未折叠蛋白反应（UPR）是在ER和细胞核之间通信的信号转导途径。在酵母中，大量的UPR靶基因已被实验确定，但先前表征的未折叠蛋白反应元件（UPRE），在UPR靶基因KAR 2的启动子中发现的上游激活序列（UAS），不能解释这组中大多数基因的转录调控。为了解决这个难题，我们通过计算分析了UPR靶基因的启动子，确定了统计上过度代表的候选UAS短序列。我们测试了这些候选UAS中最有前途的生物活性，并确定了两种新的UPR，这是必要的和足够的UPR激活启动子。一个新的图案的激活剂的遗传筛选显示，转录因子Gcn4p在UPR中起着重要的和以前未被认识到的作用：Gcn4p和它的激活剂Gcn2p是在ER应激过程中诱导大多数UPR靶基因所必需的。Hac1p和Gcn4p都结合靶基因启动子以刺激转录诱导。响应于变化的生理条件的Gcn4p水平的调节可以作为调节UPR的另外的手段。Gcn4p在酵母UPR中的作用的发现揭示了额外的复杂性水平，并证明了酵母和后生动物细胞之间的信号通路的惊人保守性。酵母未折叠蛋白反应激活了大量的靶基因，但在一个靶基因KAR 2的启动子中发现的特征元件不能解释大多数靶基因。使用计算和实验方法，作者确定了其他元素，以及GCN 4p在响应中的作用。
Eukaryotic cells respond to accumulation of unfolded proteins in the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR), a signal transduction pathway that communicates between the ER and the nucleus. In yeast, a large set of UPR target genes has been experimentally determined, but the previously characterized unfolded protein response element (UPRE), an upstream activating sequence (UAS) found in the promoter of the UPR target gene KAR2, cannot account for the transcriptional regulation of most genes in this set. To address this puzzle, we analyzed the promoters of UPR target genes computationally, identifying as candidate UASs short sequences that are statistically overrepresented. We tested the most promising of these candidate UASs for biological activity, and identified two novel UPREs, which are necessary and sufficient for UPR activation of promoters. A genetic screen for activators of the novel motifs revealed that the transcription factor Gcn4p plays an essential and previously unrecognized role in the UPR: Gcn4p and its activator Gcn2p are required for induction of a majority of UPR target genes during ER stress. Both Hac1p and Gcn4p bind target gene promoters to stimulate transcriptional induction. Regulation of Gcn4p levels in response to changing physiological conditions may function as an additional means to modulate the UPR. The discovery of a role for Gcn4p in the yeast UPR reveals an additional level of complexity and demonstrates a surprising conservation of the signaling circuit between yeast and metazoan cells. The yeast unfolded protein response activates a large set of target genes, but a characterized element found in the promoter of one target, KAR2, cannot account for most targets. Using computational and experimental methods, the authors identify additional elements, as well a role for GCN4p in the response
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DOI：
10.1073/pnas.90.10.4616
发表时间：
1993-05-15
影响因子：
11.1
作者：
DEVER, TE;CHEN, JJ;HINNEBUSCH, AG
通讯作者：
HINNEBUSCH, AG
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
16
作者：
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通讯作者：
Ron, D
DOI：
10.1073/pnas.180265397
发表时间：
2000-08-29
影响因子：
11.1
作者：
Bussemaker, HJ;Li, H;Siggia, ED
通讯作者：
Siggia, ED