<br>UPR 效应蛋白 ATF6 和 XBP1 的表达通过激活 PERK 信号传导减少结直肠癌细胞增殖和干性。,Cell Death & Disease

当前位置： X-MOL 学术 › Cell Death Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

UPR 效应蛋白 ATF6 和 XBP1 的表达通过激活 PERK 信号传导减少结直肠癌细胞增殖和干性。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-06-21 , DOI: 10.1038/s41419-019-1729-4
Claudia N Spaan ₁ , Wouter L Smit ₁ , Jooske F van Lidth de Jeude ₁ , Bartolomeus J Meijer ₁ , Vanesa Muncan ₁ , Gijs R van den Brink _{1,

2} , Jarom Heijmans _{1,

3}

Affiliation

未折叠蛋白反应 (UPR) 通过其下游分支、PERK-eIF2α 信号传导、IRE1α-XBP1 信号传导和 ATF6 信号传导发挥作用。在肠道中，通过激酶 PERK 激活 UPR 会导致肠上皮干细胞和结肠癌干细胞的分化，而 XBP1 的缺失会导致干性增加和腺瘤发生。 XBP1 和 ATF6 的下游激活如何影响肠道干性和增殖仍然很大程度上未知。我们生成了结直肠癌细胞 (LS174T)，该细胞含有强力霉素诱导表达的 XBP1(s) 或 ATF61-373 活性形式。 XBP1 或 ATF6 的激活会导致细胞增殖减少和肠上皮干性标记物的表达减少。此外，XBP1和ATF6的激活减少了整体蛋白质合成并降低了UPR激活的阈值。 XBP1 介导的干性和增殖丧失是由 PERK-eIF2α 信号传导交叉激活引起的，并且可以通过 eIF2α 磷酸酶 GADD34 的组成型表达来挽救。因此，我们发现 XBP1 和 ATF6 的强制激活会导致干性和增殖的减少。我们揭示了 XBP1 和 PERK-eIF2α 信号传导之间的新型相互作用。

"点击查看英文标题和摘要"

Expression of UPR effector proteins ATF6 and XBP1 reduce colorectal cancer cell proliferation and stemness by activating PERK signaling.

The unfolded protein response (UPR) acts through its downstream branches, PERK-eIF2α signaling, IRE1α-XBP1 signaling and ATF6 signaling. In the intestine, activation of the UPR through the kinase PERK results in differentiation of intestinal epithelial stem cells and colon cancer stem cells, whereas deletion of XBP1 results in increased stemness and adenomagenesis. How downstream activation of XBP1 and ATF6 influences intestinal stemness and proliferation remains largely unknown. We generated colorectal cancer cells (LS174T) that harbor doxycycline inducible expression of the active forms of either XBP1(s) or ATF61-373. Activation of either XBP1 or ATF6 resulted in reduced cellular proliferation and reduced expression of markers of intestinal epithelial stemness. Moreover, XBP1 and ATF6 activation reduced global protein synthesis and lowered the threshold for UPR activation. XBP1-mediated loss of stemness and proliferation resulted from crossactivation of PERK-eIF2α signaling and could be rescued by constitutive expression of eIF2α phosphatase GADD34. We thus find that enforced activation of XBP1 and ATF6 results in reduction of stemness and proliferation. We expose a novel interaction between XBP1 and PERK-eIF2α signaling.

更新日期：2019-06-24

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南