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XBP1-KLF9 axis acts as a molecular rheostat to control the transition from adaptive to cytotoxic unfolded protein response

ABSTRACT: Elevation of ER stress above a critical threshold causes accumulation of XBP1s protein sufficient for binding to the promoter and activation of a gene encoding a transcription factor KLF9. In turn, KLF9 induces expression of two regulators of ER calcium storage, TRIM38B and ITRP1, facilitating additional calcium release from ER, exacerbation of ER stress, and cell death.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119427 | GEO | 2018/12/06

REPOSITORIES: GEO

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XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response.

Project description:Transcription factor XBP1s, activated by endoplasmic reticulum (ER) stress in a dose-dependent manner, plays a central role in adaptive unfolded protein response (UPR) via direct activation of multiple genes controlling protein refolding. Here, we report that elevation of ER stress above a critical threshold causes accumulation of XBP1s protein sufficient for binding to the promoter and activation of a gene encoding a transcription factor KLF9. In comparison to other XBP1s targets, KLF9 promoter contains an evolutionary conserved lower-affinity binding site that requires higher amounts of XBP1s for activation. In turn, KLF9 induces expression of two regulators of ER calcium storage, TMEM38B and ITPR1, facilitating additional calcium release from ER, exacerbation of ER stress, and cell death. Accordingly, Klf9 deficiency attenuates tunicamycin-induced ER stress in mouse liver. These data reveal a role for XBP1s in cytotoxic UPR and provide insights into mechanisms of life-or-death decisions in cells under ER stress.

| S-EPMC6251307 | biostudies-literature

Contribution of the Unfolded Protein Response (UPR) transcription factor XBP1 to brain aging

Project description:In this project we aimed to evaluate the contribution of endoplasmic reticulum stress sensor IRE1 and its downstream transcription factor XBP1s to mammalian brain aging. We compared traits associated to aging at behavioral, electrophysiological, morphological and proteomic levels. We used transgenic animals overexpressing XBP1s in brain tissue and also wild type animals injected with adeno-associated virus to overexpress XBP1s in the brain during aging.

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Effect of neuron-specific spliced XBP1 (XBP1s) overexpression on gene expression in the mouse brain

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2022-10-22 | GSE160263 | GEO

Profiling gene expression in 32Dcl3 cells following Xbp1 retrovirus vector transfection

Project description:The significant changes of hematopoietic cells induced by Xbp1S expression indicate that there is global alteration in gene expression. UPR induces transcription of Xbp1, and phosphorylation of the ER transmembrane kinase IRE1 initiates UPR-mediated mRNA splicing of Xbp1, resulting in the production of Xbp1S, an active form of a basic leucine zipper transcription factor. In the present study, Xbp1S retrovirus vector infected 32cl3 cells show cell cycle arrest and myeloid differentiation. Xbp1S may modulate important genes of differentiation and the cell cycle. RNA samples extracted from 32Dcl3 cells with pMIG (empty vector), pMY-Xbp1U (unspliced form) and pMY-Xbp1S (spliced form) retroviral vector transfected cells were subjected to expression profiling using the Affymetrix GeneChip microarray system.

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Profiling gene expression in 32Dcl3 cells following Xbp1 retrovirus vector transfection

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XBP1-KLF9 axis acts as a molecular rheostat to control the transition from adaptive to cytotoxic unfolded protein response

Project description:XBP1-KLF9 axis acts as a molecular rheostat to control the transition from adaptive to cytotoxic unfolded protein response

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Klf9 is essential for cardiac mitochondrial homeostasis

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Global changes in gene expression in primary keratinocytes after KLF9 overexpression

Project description:To identify putative target genes of the transcription factor Klf9 in primary keratinocytes we over-expressed Klf9 in these cells using a lentiviral delivery system. We detected several hundred genes that show differential expression levels following ectopic Klf9 expression including several genes that are involved in proliferation and cell cycle control. These results allow insights into the mechanisms by which Klf9 regulates proliferation in primary keratinocytes. Primary human neonatal foreskin keratinocytes were infected with equal viral titers of a GFP and KLF9 expression construct, respectively. Cells were harvested 2,4 and 7 days after infection and total RNA was used to perform whole genome microarray analysis.

2012-07-30 | E-GEOD-36014 | biostudies-arrayexpress

Transcription profiling of jejunums from wild type and Klf9-/- mice to investigate the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination.

Project description:Kruppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation and cell fate in brain and uterus. Using Klf9 null mutant mice, we have investigated the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt stem/transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of Goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was demonstrated by BrdU labeling. Results suggest that Klf9 controls the elaboration, from small intestine smooth muscle, of molecular mediator(s) of crypt cell proliferation and lineage determination, and of villus cell migration. Experiment Overall Design: Total RNA was extracted in parallel from the jejunums of five WT and five Klf9-/- male mice (PND 30) using TRIzol reagent (Invitrogen, Carlsbad, CA). Conversion of each RNA preparation to corresponding fragmented cRNA. Fifteen ug of each cRNA was hybridized for 16 hours to an Affymetrix mouse 430A GeneChip. Ten GeneChips (each corresponding to a single animal) were hybridized, washed and scanned in parallel. Following the wash, signal amplification, and signal detection steps, GeneChips were scanned (Agilent GeneArray laser scanner) and the resultant images quantified using Affymetrix MAS 5.0 software.

2007-11-15 | E-GEOD-6443 | biostudies-arrayexpress

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2021-02-10 | GSE166417 | GEO

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