Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The transcription factor IRF4 represses pro-apoptotic BMF and BIM to licence Multiple Myeloma survival

ABSTRACT: The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for the survival of the plasma cell malignancy multiple myeloma (MM), although the mechanism by which this is achieved remains unknown. Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 genetic ablation of IRF4 across several MM cells lines. We report that IRF4 loss uniformly resulted in the upregulation of two related pro-apoptotic proteins belonging to the BH3-only subgroup of the BCL2 family: BCL2 modifying factor (BMF) and BCL2 interacting mediator of cell death (BIM). Direct IRF4 binding was identified in the proximal promoter region of both genes. Remarkably, genetic ablation of BMF alone or in combination with BIM largely prevented the cell death that follows IRF4 inactivation, establishing that IRF4 maintains MM survival through the direct transcriptional repression of BMF and BIM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148984 | GEO | 2022/12/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Gene expression of attached and suspended Bim-/- Bmf-/- murine kidney epithelial cells

Project description:Suspension-induced cell death, or anoikis, is implicated in different stages of breast development as well as tumor progression and metastasis. The pro-apoptotic BH3-only proteins BIM and BMF are known positive regulators of anoikis. We examined the gene expression changes that occur in BIM-/- BMF-/- cells during attachment and suspension. This study is supplemental to our work establishing a role for JNK in anoikis (Girnius N, Davis RJ. 2017. JNK promotes epithelial cell anoikis by transcriptional and post-translational regulation of BH3-only proteins. (2017) Cell Reports 21: 1910-1921; doi: 10.1016/j.celrep.2017.10.067)

2018-02-28 | GSE111221 | GEO

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis

Project description:Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.

2024-09-24 | PXD045034 | Pride

JNK promotes epithelial cells anoikis by transcriptional and post-translational regulation of BH3-only proteins

Project description:Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK-deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that JNK acts through a BAK/BAX-dependent apoptotic pathway by increasing BIM expression and phosphorylating BMF leading to death of detached epithelial cells.

2017-11-14 | GSE88856 | GEO

Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM

Project description:Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. De-repression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance “free” cellular BIM levels both led to re-sensitization of mesenchymal EGFR mutant cancers to EGFR inhibitors. This relationship between EMT and loss of BIM is not restricted to EGFR mutant lung cancers as it was also observed in KRAS mutant lung cancers and large datasets including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies.

2018-01-01 | GSE106896 | GEO

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis.

2023-09-08 | GSE242368 | GEO

Gene expression of attached and suspended Bim-/- Bmf-/- murine kidney epithelial cells

Project description:Gene expression of attached and suspended Bim-/- Bmf-/- murine kidney epithelial cells

| PRJNA436181 | ENA

Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma

2013-03-13 | GSE43878 | GEO

JNK activation of BIM promotes hepatic oxidative stress, steatosis and insulin resistance in obesity

Project description:The BCL-2 family are crucial regulators of the mitochondrial pathway of apoptosis in normal physiology and disease. Besides their role in cell death, BCL-2 proteins have been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism. However, it remains unclear whether these proteins have a physiological role in glucose homeostasis and metabolism in vivo. Here we report that fat accumulation in the liver increases JNK-dependent BIM expression in hepatocytes. We generated liver-specific BIM knockout (BLKO) mice to determine the consequences of hepatic BIM deficiency in diet-induced obesity. BLKO mice had lower hepatic lipid content, increased insulin signalling and improved global glucose metabolism. Consistent with this, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Moreover, oxidative stress, oxidation of protein tyrosine phosphatases and activation of PPAR-g/STAT1/CD36 were decreased in livers/hepatocytes from BLKO mice, suggesting a mechanism for their metabolic phenotype. Importantly, adenovirus-mediated knockdown of BIM reduced fat accumulation and improved insulin sensitivity in high fat fed mice. Our data postulate BIM as a novel therapeutic target regulating mitochondrial bioenergetics and liver function in obesity.

2017-09-21 | GSE102982 | GEO

IRF4 contributes to chemoresistance in IGH-BCL2 positive diffuse large B-cell lymphomas by mediating BCL2 induced SOX9 expression

Project description:SOX9 was identified as a prognostic biomarker particularly in IGH-BCL2 translocated germinal center B cell (GCB) subtypes of the diffuse large B cell lymphoma (DLBCL) and plays a vital role in lymphomagenesis. However, the molecular mechanism that modulating the aberrant expression of SOX9 in this DLBCL subset remains unknown. We have demonstrated that SOX9 enhanced IGH-BCL2 positive DLBCL subset resistance to either chemotherapy or BCL2 inhibitor. Moreover, we found that inhibition of BCL2 downregulates SOX9 in IGH-BCL2 positive DLBCL subset. We further identified that IRF4 is a key regulator to mediate BCL2 induced SOX9 expression, alongside with the chip-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promote IRF4 entry into the nucleus by enhancing its protein stability, via downregulating of proteosome ubiquitination process, and, therefore, enforce SOX9-mediated phenotypes. Finally, we showed in DLBCL cell lines and xenografted mice model that in vivo inhibition of IRF4 with hIRF4 antisense oligonucleotide (ASO) repressed lymphomagenesis and DLBCL chemoresistance. Altogether, our data support the conclusion that IRF4 plays an essential role in BCL2 induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapse and refractory DLBCL in the future.

2024-09-30 | GSE278092 | GEO

Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma

Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma. To generate a gene expression signature of caspase 10 signaling in multiple myeloma, cell lines (SKMM1 n=16, KMS12 n=8 and H929 n=12) were transduced with retroviral vectors expressing either shCasp10-2 or shCasp10-3. Similarly, lymphoma cell lines (OCI-Ly7 n=2 and OCI-Ly19 n=2) were transduced and used as a control. Following puromycin selection, shRNA expression was induced for 24 to 120 hours and gene expression was measured, comparing uninduced (Cy3) to induced (Cy5) cells, using lymphochip microarrays. Biological repeats were performed of H929 and SKMM1 samples.

2013-03-13 | E-GEOD-43878 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data