Endoplasmic reticulum stress responses

Schröder, Martin

doi:10.1007/s00018-007-7383-5

Cited by 603 publications

(547 citation statements)

References 295 publications

(408 reference statements)

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“…Pancreatic acinar cells lacking MIST1 lose nearly all ability to secrete digestive enzymes and have significantly increased basal cellular autophagy, characteristics that are found under ER stress conditions as well as in cells lacking Xbp1 (12,21,24,49,50). The observed XBP1-mediated induction of Mist1 during ER stress, coupled with the marked reduction in secretion associated with Mist1 KO acinar cells (12,21), prompted us to investigate if MIST1 might regulate a previously uncharacterized set of gene targets needed for both basal and ER stress-induced maintenance of the secretory machinery.…”

Section: Resultsmentioning

confidence: 99%

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

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Section: Resultsmentioning

confidence: 99%

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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“…[22][23][24][25][26] The ER stress is generally activated in response to various stressful conditions, such as hypoxia, the accumulation of unfolded or misfolded proteins, the alterations of calcium homeostasis, low glucose levels and others. [8][9][10] Recent reports have shown that ER stress occurs during osteogenic differentiation. [17][18][19][20][21] ER stressinduced apoptosis of osteoblasts has also been implicated in the pathogenesis of osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts

Guo

Sun

et al. 2014

Laboratory Investigation

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Although many studies have suggested that estrogen prevents postmenopausal bone loss partially due to its anti-apoptosis effects in osteoblasts, the underlying mechanism has not been fully elucidated. In the present study, we found that 17b-estradiol (17b-E 2 ), one of the primary estrogens, inhibited endoplasmic reticulum (ER) stress-induced apoptosis in MC3T3-E1 cells and primary osteoblasts. Interestingly, 17b-E 2 -promoted Grp78 induction, but not CHOP induction in response to ER stress. We further confirmed that Grp78-specific siRNA reversed the inhibition of 17b-E 2 on ER stress-induced apoptosis by activating caspase-12 and caspase-3. Moreover, we found that 17b-E 2 markedly increased the phosphorylated TFII-I levels and nuclear localization of TFII-I in ER stress conditions. 17b-E 2 stimulated Grp78 promoter activity in a dose-dependent manner in the presence of TFII-I and enhanced the binding of TFII-I to the Grp78 promoter. In addition, 17b-E 2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity in MC3T3-E1 cells. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked 17b-E 2 -induced TFII-I phosphorylation and Grp78 expression in response to ER stress. Together, 17b-E 2 protected MC3T3-E1 cells against ER stress-induced apoptosis by promoting Ras-ERK1/2-TFII-I signaling pathway-dependent Grp78 induction.Laboratory Investigation (2014) 94, 906-916;

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“…6a) and 3.3-folds on day 6 with respect to day 1. In comparison, mRNA of GRP94, which binds to partial folded proteins and acts sequentially after GRP78 (Schröder 2008), shows an increase of 2.3-fold on day 3 (Fig. 6b).…”

Section: Early Upregulation Of Chaperones In High Producermentioning

confidence: 95%

“…Homeostasis in ER is maintained by coordinated regulation between three pathways (see Fig. 1): endoplasmic reticulum associated folding (ERAF), ER associated protein degradation (ERAD) and unfolded protein response pathway (UPR) (Schröder 2008). In the event of accumulation of unfolded protein in the ER, the UPR signaling cascade is activated in response to ER stress.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of unfolded protein response in recombinant CHO cells

Prashad

Mehra

2014

Cytotechnology

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Genes in the protein secretion pathway have been targeted to increase productivity of monoclonal antibodies in Chinese hamster ovary cells. The results have been highly variable depending on the cell type and the relative amount of recombinant and target proteins. This paper presents a comprehensive study encompassing major components of the protein processing pathway in the endoplasmic reticulum (ER) to elucidate its role in recombinant cells. mRNA profiles of all major ER chaperones and unfolded protein response (UPR) pathway genes are measured at a series of time points in a high-producing cell line under the dynamic environment of a batch culture. An initial increase in IgG heavy chain mRNA levels correlates with an increase in productivity. We observe a parallel increase in the expression levels of majority of chaperones. The chaperone levels continue to increase until the end of the batch culture. In contrast, calreticulin and ERO1-L alpha, two of the lowest expressed genes exhibit transient time profiles, with peak induction on day 3. In response to increased ER stress, both the GCN2/PKR-like ER kinase and inositol-requiring enzyme-1alpha (Ire1a) signalling branch of the UPR are upregulated. Interestingly, spliced X-Box binding protein 1 (XBP1s) transcription factor from Ire1a pathway is detected from the beginning of the batch culture. Comparison with the expression levels in a low producer, show much lower induction at the end of the exponential growth phase. Thus, the unfolded protein response strongly correlates with the magnitude and timing of stress in the course of the batch culture.

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Endoplasmic reticulum stress responses

Cited by 603 publications

References 295 publications

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts

Dynamics of unfolded protein response in recombinant CHO cells

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