Identification of Mitogen-Activated Protein Kinase Signaling Pathways That Confer Resistance to Endoplasmic Reticulum Stress in Saccharomyces cerevisiae

Abstract

Hypoxia activates all components of the unfolded protein response (UPR), a stress response initiated by the accumulation of unfolded proteins within the endoplasmic reticulum (ER). Our group and others have shown previously that the UPR, a hypoxia-inducible factor -independent signaling pathway, mediates cell survival during hypoxia and is required for tumor growth. Identifying new genes and pathways that are important for survival during ER stress may lead to the discovery of new targets in cancer therapy. Using the set of 4,728 homozygous diploid deletion mutants in budding yeast, Saccharomyces cerevisiae, we did a functional screen for genes that conferred resistance to ER stress -inducing agents. Deletion mutants in 56 genes showed increased sensitivity under ER stress conditions. Besides the classic UPR pathway and genes related to calcium homeostasis, we report that two additional pathways, including the SLT2 mitogen-activated protein kinase (MAPK) pathway and the osmosensing MAPK pathway, were also required for survival during ER stress. We further show that the SLT2 MAPK pathway was activated during ER stress, was responsible for increased resistance to ER stress, and functioned independently of the classic IRE1/HAC1 pathway. We propose that the SLT2 MAPK pathway is an important cell survival signaling pathway during ER stress. This study shows the feasibility of using the yeast deletion pool to identify relevant mammalian orthologues of the UPR. (Mol Cancer Res 2005;3(12):669 -77)

Targeting XBP-1 as a novel anti-cancer strategy

“…This initial observation was further substantiated by experiments showing that wild-type MEFs stably transfected with a vector expressing small inhibitory RNA for XBP-1 were also impaired in tumor growth. 12 Moreover, these studies have also been conducted in a human fibrosarcoma tumor cell line 47 and several pancreatic adenocarcinoma cell lines (data not shown), demonstrating the general applicability of these results. Similar results were obtained in tumor cells expressing dominant negative inhibitors of IRE1 (manuscript in preparation).…”

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

“…To determine if the upregulation of these ER stress-responsive transcripts in a ccr4⌬ mutant would result in phenotypic consequences consistent with ER stress response engagement, we looked to studies of ER stress phenotypes in the model yeast S. cerevisiae, which demonstrate that constitutive activation of the UPR is accompanied by resistance to tunicamycin (4). The sensitivities to tunicamycin of the wild type and the ccr4⌬ mutant were compared using a spot plate assay.…”

Tumor cell dormancy induced by p38SAPK and ER-stress signaling: An adaptive advantage for metastatic cells?

“…It is plausible that ER-stress activation of p38 signaling serves also as survival signal 45 since p38 was shown to be necessary for the survival to ER-stress both in HeLa human cervical carcinoma cells 59 and Saccharomyces cerevisiae. 60 An alternative survival mechanism could be attributed to IRE1-mediated activation of TRAF2, which activates the survival transcription factor NF-κB. 61,62 The fact that MEFs lacking TRAF2 are more susceptible to ER-stress than their WT counterparts, 63 supports this hypothesis.…”