A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1207135 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31908015.fastq.gz | Fastqsanger.gz | |||
| SRR31908016.fastq.gz | Fastqsanger.gz | |||
| SRR31908017.fastq.gz | Fastqsanger.gz | |||
| SRR31908018.fastq.gz | Fastqsanger.gz | |||
| SRR31908019.fastq.gz | Fastqsanger.gz |
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Project description:Endoplasmic-reticulum resident inositol-requiring enzyme 1alpha(IRE1) supports protein homeostasis via a cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and of RNA decay. We discovered that some cancer cells require IRE1 but not its enzymatic activity. IRE1 knockdown, but not enzymatic inhibition or XBP1 disruption, increased DNA damage and chromosome instability while engaging the TP53 pathway and cyclin-dependent kinase inhibitors, and attenuated cell cycle progression. IRE1 depletion downregulated factors involved in chromosome replication and segregation and in chromatin remodeling. Immunoelectron microscopy indicated that endogenous IRE1 can localize to the nuclear envelope. Thus, cancer cells can require IRE1 either enzymatically or nonenzymatically, with significant implications for IRE1's biological role and therapeutic targeting.
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Project description:<p>The Unfolded Protein Response (UPR) is a retrograde, ER-to-nucleus, signalling pathway which is conserved across kingdoms. In plants, it contributes to development, reproduction, immunity and tolerance to abiotic stress. This metabolomic dataset was produced from 14-day-old Arabidopsis thaliana seedlings challenged by tunicamycin (Tm), an antibiotic inhibiting Asn-linked glycosylation in the endoplasmic reticulum (ER), causing an ER stress and eventually activating the UPR. Wild-type (WT), double mutant deficient for two main actors of the UPR (INOSITOL-REQUIRING ENZYME 1A [IRE1A] and INOSITOL-REQUIRING ENZYME 1B [IRE1B]), as well as doubles mutants complemented with either of the WT IRE1 alleles were used as genetic backgrounds in our experimental setup. This allows to distinguish among differentially-overaccumulated metabolites which ones are dependent on IRE1A and/or IRE1B. Also, shoots and roots were harvested separately to determine organ-specific metabolic responses to Tm.</p>
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Project description:Multiple Myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting
plasma cells. MM often co-opts the endoplasmic-reticulum (ER) stress mitigator, inositol
requiring enzyme 1 (IRE1), to sustain malignant growth. While certain MMs require enzymatic
IRE1-dependent activation of the ER-homeostatic transcription factor XBP1s, others display
nonenzymatic dependency on IRE1 that is not yet mechanistically understood. Interferon
regulatory factor 4 (IRF4) stimulates gene programs that promote immune-cell proliferation and cell cycle control by IRE1 in MM. Here we show that IRF4 acts as a key conduit of nonenzymatic cell cycle control by IRE1 in MM. IRE1 silencing increased inhibitory phosphorylation of IRF4, disrupting its chromatin-binding activity and mRNA transcription. IRF4 knockdown recapitulated, whereas IRF4 repletion reversed the anti-proliferative phenotype of IRE1 silencing. Functional studies revealed that IRF4 engages the E2F1 and CDC25A genes and promotes CDK2 activation to drive cell cycle progression. Our results advance mechanistic understanding of IRE1 and IRF4 in MM.
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