Dataset Information

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

ABSTRACT: The unfolded protein response (UPR) acts through its downstream branches, PERK-eIF2? signaling, IRE1?-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 ATF6^1-373. 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-eIF2? signaling and could be rescued by constitutive expression of eIF2? 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-eIF2? signaling.

SUBMITTER: Spaan CN

PROVIDER: S-EPMC6588629 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Spaan Claudia N CN Smit Wouter L WL van Lidth de Jeude Jooske F JF Meijer Bartolomeus J BJ Muncan Vanesa V van den Brink Gijs R GR Heijmans Jarom J

Cell death & disease 20190621 7

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 co ...[more]

PMID: 31227689

Similar Datasets

Project description:BackgroundAutophagy and ER stress are involved in maintaining some well-orchestrated mechanisms aimed at either restoring cellular homeostasis or performing cell death. Autophagy is a well-defined process which governs overall cellular stress outcomes. Selective degradation of the ER mediated by autophagy occurs through a specific type of autophagy called ER-phagy, which ensures ER protein homeostasis.MethodsImmunoblotting and RT-PCR were used to evaluate the expression of ATG5 and ATG7 in chondrocyte. Western blotting, Flow cytometry,immunofluorescence cell staining and confocal microscope were used to examine the effect of ATG5 and ATG7 on autophagy, ER stress, cell apoptosis and cell proliferation. Transmission electron microscope and confocal microscope were performed to visualize the autophagy flux and autolysosome formation. The role of ATG5 and ATG7 overexpression on the PERK pathway inhibitor were detected by immunoblotting and treatment with inhibitors.ResultsIn current study, we demonstrated that Tm-induced ER stress can activate autophagy while Rapamycin-induced autophagy can inhibit ER stress in chondrocyte. Autophagy related protein ATG5 or ATG7 can promote autophagy and inhibit ER stress individually, and their combined effect can further improve the autophagy enhancement and the ER stress repression. Moreover, ATG5, ATG7 and ATG5 + ATG7 lead cells into more S phase, increase the number of S phase and inhibit apoptosis as well. ATG5, ATG7 and ATG5 + ATG7 regulate autophagy, ER stress, apoptosis and cell cycle through PERK signaling, a vital UPR branch pathway.ConclusionsATG5 and ATG7 connect autophagy with ER stress through PERK signaling. The protective effect of ATG5/7 overexpression on chondrocyte survival relys on PERK signaling. The effect of siPERK and siNrf2 on the cytoprotective effect of ATG5/7 are of synergism, while the effect of siPERK and siATF4 are of antagonism. PERK signal may be the pivot for autophagy, ER homeostasis and ER-phagy in chondrocyte.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets