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GSE44951
Homo sapiens
15 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation.
Publication Title
Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation.
Publication Title
Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
Illumina HiSeq 2000
Description
The unfolded protein response (UPR), as its name implies, safeguards secretory pathway proteostasis. The most ancient arm of the UPR, the IRE1-activated, XBP1s-mediated transcriptional response, has roles in secretory pathway maturation beyond resolving proteostatic stress. Understanding the consequences of XBP1s' transcriptional output for cellular processes is critical for elucidating mechanistic connections between XBP1s and development, immunity, and disease. Here, we show that a key functional consequence of XBP1s activation is a cell type-dependent shift in the distribution of N-glycan structures on endogenous membrane and secreted proteomes. XBP1s activity decreases sialylation of tri- and tetra-antennary N-glycans in the HEK293 membrane proteome and secretome, while substantially increasing the population of high mannose N-glycans only in the secretome. Related, but distinctive, signatures in the HEK293 N-glycome are observed when the entire UPR is activated in a stress-dependent manner using thapsigargin. In HeLa cells, stress-independent XBP1s activation increases the population of cell surface high mannose N-glycans and tetra-antennary N-glycans. mRNA profiling experiments suggest that the XBP1s-mediated remodeling of the N-glycome may re-flect a coordinated consequence of transcriptional resculpting of the N-glycan maturation pathway by XBP1s. The discovery of XBP1s-induced N-glycan structural remodeling on a glycome-wide scale suggests that XBP1s is a master regulator of N-glycan maturation. Moreover, because the sugars on cell surface proteins or on those proteins secreted from an XBP1s-activated cell can be molecularly distinct from those of an unactivated cell, these findings reveal a potential new mechanism for translating intracellular stress signaling pathways into al-tered interactions with the extracellular environment. Overall design: Three biological replicates of HeLaXBP1s cells treated with DMSO vehicle, 1 ug/ml dox or 750 nM Thapsigargin.
Publication Title
XBP1s activation can globally remodel N-glycan structure distribution patterns.
Sample Metadata Fields
Cell line, Treatment, Subject, Time
View Samples- Homo sapiens
- 21 Downloadable Samples
- Illumina HiSeq 2000
Description
Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. Comprehensive transcriptome analysis was employed to validate the capacity of three prioritized compounds to remodel the ER proteostasis environment, and to assess the prefential activation of ATF6 transcriptional targets relative to targets of the IRE1/XBP1s and PERK arms of the UPR. Overall design: HEK293T-Rex and HEK293-DAX cells were treated for 6 hr with vehicle (DMSO), 1 µM Tg, 10 mM TMP (in HEK293DAX), or 10 µM 132, 147 or 263 in biological triplicate at 37 °C
Publication Title
Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Rattus norvegicus
- 20 Downloadable Samples
- Affymetrix Rat Gene 1.1 ST Array (ragene11st)
Description
Identify differentially expressed genes related to the neurodegenerative process in a new animal model of hepatic encephalopathy (HE).
Publication Title
Cerebellar neurodegeneration in a new rat model of episodic hepatic encephalopathy.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Cyclin D3 is critical hematopoiesis and loss of cyclin D3 leads to resistance to transformation of bone marrow progenitors by Notch1-IC.
Publication Title
Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Activated NOTCH1 induces T-ALL in mice when transduced in bone marrow (BM) cells. T-ALL cells activate the calcineurin/NFAT pathway in vivo (Medyouf H. et al. Nat Med 2007 [PMID 17515895]).
Publication Title
Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 83 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers.
Publication Title
Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 33 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples