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ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation

ABSTRACT: ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation

PROVIDER: PRJNA735713 | ENA |

REPOSITORIES: ENA

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ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation

Project description:The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that interacts directly via feedforward and feedback reactions to regulate the body’s response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), ZBTB32 (zinc finger and BTB domain containing 32) is a transcription factor with very poorly described functional relevance in physiology. We investigated the importance of ZBTB32 on the HPA axis functioning and found that it is essential for the production of glucocorticoids (GCs) in response to starvation, because ZBTB32-/- mice fail to increase the GC production during prolonged absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32-/- mice, implicating defective cholesterol import as the cause of the poor GC synthesis. Lower GC levels in ZBTB32-/- mice are further associated with aberrations in the metabolic adaptation to starvation, which could potentially explain the progressive weight gain of ZBTB32-/- mice. Moreover, this study identifies that ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production.

2021-06-08 | GSE176277 | GEO

Exploiting crosstalk between glucocorticoid and mineralocorticoid receptors enhances glucocorticoid-induced killing of multiple myeloma cells

Project description:Long-term glucocorticoid treatment in multiple myeloma is hampered by deleterious side effects. Glucocorticoids bind to the glucocorticoid receptor (GR), which is a crucial drug target because its activation triggers myeloma cell death. The mineralocorticoid receptor (MR) is a closely related nuclear receptor but its impact on glucocorticoid responsiveness in myeloma is unknown. Here we reveal a functional crosstalk between GR and MR that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone enhances Dex-induced cell killing in (primary) myeloma cells. The crosstalk is further evidenced by an endogenous interaction between GR and MR in myeloma cells that is ligand-inducible and by a distinctive gene expression profile. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.

2023-08-23 | GSE200313 | GEO

ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation.

Project description: Not available

| S-EPMC8324811 | biostudies-literature

Crosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells

Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.

2023-10-24 | PXD043635 | Pride

IRF2BP2 Modulates the Crosstalk between Glucocorticoid and TNF Signaling

Project description:IRF2BP2 Modulates the Crosstalk between Glucocorticoid and TNF Signaling

| PRJNA512883 | ENA

IRF2BP2 Modulates the Crosstalk between Glucocorticoid and TNF Signaling

Project description:Here we have analyzed the role of interferon regulatory factor-2 binding protein-2 (IRF2BP2) in glucocorticoid and tumor necrosis factor alpha (TNF) signaling. We used ChIP-seq to analyze chromatin binding of IRF2BP2 in glucocorticoid (dexamethasone, dex) and vehicle treated HEK293 cells expressing GR (HEK293-GR). Furthermore, we used RNA-seq to analyze how silencing of IRF2BP2 modulates transcriptional responses to dex treatment in HEK293-GR cells, and dex, TNF and co-treatment (dex and TNF, DT) in A549 cells.

2019-06-03 | GSE124636 | GEO

Short-term Starvation vs. Normal Diet Before Chemotherapy of Solid Tumors

Project description:Recent pre-clinical data provide strong evidence that short-term starvation before the administration of cytostatic drugs for the chemotherapy of solid tumors leads to significantly higher efficacy and lower toxicity levels. However, these findings have so far not been validated in patients. The aim of this trial is to provide first clinical evidence regarding the impact of pre-chemotherapeutic short-term starvation on response to therapy (primary endpoint). Additionally, progression-free survival, adverse events, and overall survival will be monitored (secondary endpoints). In perspective, short-term starvation before chemotherapy could represent a simple and secure way to improve both efficacy and tolerance of chemotherapies at low cost.

| 2202552 | ecrin-mdr-crc

Nascent transcript analysis of glucocorticoid crosstalk with TNF in Beas-2B airway epithelial cells

Project description:Nascent transcript analysis of glucocorticoid crosstalk with TNF in Beas-2B airway epithelial cells

| PRJNA514316 | ENA

Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

Project description:Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

| PRJNA432243 | ENA

Histone arginine methyltransferase CARM1 Is Crucial for Epigenetic Regulation of Starvation-induced Autophagy

Project description:Autophagy is a highly conserved self-digestion process, essential to maintain homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well-studied, molecular basis for the epigenetic regulation of autophagy is poorly understood. Here, we identify histone arginine methyltransferase CARM1 as a critical component of autophagy. We found that nutrient starvation increased CARM1 protein level and subsequently histone H3R17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional coactivator function on autophagy-related genes and lysosomal genes through TFEB. Our findings demonstrate a previously unrecognized role of CARM1-dependent histone arginine methylation as a critical nuclear event of autophagy.

2016-06-17 | GSE72901 | GEO

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