Activation of the Mitochondrial Stress Response in Clear Cell Renal Cell Carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134933 | GEO | 2020/08/01
REPOSITORIES: GEO
Similar Datasets
Project description:The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of Growth Arrest and DNA Damage inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We established that the 3' untranslated region of PPP1R15A mRNA contains an active AU-rich element recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a key step in establishing the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
2024-03-19 | GSE261399 | GEO
Project description:Vitamin A deficiencies and insufficiencies affect hundreds of millions of people in both developing and developed countries. These individuals experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared to those who are vitamin A sufficient. Previously, our laboratory has demonstrated that vitamin A-deficient (VAD) mice have significantly impaired virus-specific IgA and CD8+ T cell responses in the airways. Here we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared to control vitamin A-sufficient animals. Cytokines/chemokines that are reproducibly upregulated at the gene expression and protein levels include IFNγ and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box (Fox)P3+ T cell frequencies, we found no reduction in FoxP3+ T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that virus infection and viral antigen persistence were enhanced on day 10 post-infection in VAD animals compared to controls, and that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of virus infections in patients with VAD; efforts to enhance FoxP3+ T cell frequencies and quell immune effectors might in some cases exacerbate disease if virus has not been cleared. We used microarrays to explore the gene expression profiles differentially expressed in nasal-associated lymph tissue (NALT) lymphocytes from vitamin A-sufficient and vitamin A-deficient mice following infection with Sendai virus.
2016-02-11 | E-GEOD-65805 | biostudies-arrayexpress
Project description:Epigenetic regulations, such as DNA methylation and microRNAs, play an important role in renal fibrosis. Here, we report the regulation of microRNA-219a-2 (mir-219a-2) by DNA methylation in fibrotic kidneys, unveiling the crosstalk between these epigenetic mechanisms. Through genome-wide DNA methylation analysis and pyro-sequencing, we detected the hypermethylation of mir-219a-2 in renal fibrosis induced by unilateral ureter obstruction (UUO) or renal ischemia/reperfusion, which was accompanied by a significant decrease in mir-219a-5p expression. Functionally, overexpression of mir-219a-2 enhanced fibronectin induction during hypoxia or TGF-b1 treatment of cultured renal cells. In mice, inhibition of mir-219a-5p suppressed fibronectin accumulation in UUO kidneys. ALDH1L2 was identified to be the direct target gene of mir-219a-5p in renal fibrosis. Mir-219a-5p suppressed ALDH1L2 expression in cultured renal cells, while inhibition of mir-219a-5p prevented the decrease of ALDH1L2 in UUO kidneys. Knockdown of ALDH1L2 enhanced PAI-1 induction during TGF-b1 treatment of renal cells, which was associated with fibronectin expression. In conclusion, the hypermethylation of mir-219a-2 in response to fibrotic stress attenuates mir-219a-5p expression and induces the up-regulation of its target gene ALDH1L2, which may reduce fibronectin deposition by suppressing PAI-1.
2023-11-01 | GSE236018 | GEO
Project description:Epigenetic regulations, such as DNA methylation and microRNAs, play an important role in renal fibrosis. Here, we report the regulation of microRNA-219a-2 (mir-219a-2) by DNA methylation in fibrotic kidneys, unveiling the crosstalk between these epigenetic mechanisms. Through genome-wide DNA methylation analysis and pyro-sequencing, we detected the hypermethylation of mir-219a-2 in renal fibrosis induced by unilateral ureter obstruction (UUO) or renal ischemia/reperfusion, which was accompanied by a significant decrease in mir-219a-5p expression. Functionally, overexpression of mir-219a-2 enhanced fibronectin induction during hypoxia or TGF-b1 treatment of cultured renal cells. In mice, inhibition of mir-219a-5p suppressed fibronectin accumulation in UUO kidneys. ALDH1L2 was identified to be the direct target gene of mir-219a-5p in renal fibrosis. Mir-219a-5p suppressed ALDH1L2 expression in cultured renal cells, while inhibition of mir-219a-5p prevented the decrease of ALDH1L2 in UUO kidneys. Knockdown of ALDH1L2 enhanced PAI-1 induction during TGF-b1 treatment of renal cells, which was associated with fibronectin expression. In conclusion, the hypermethylation of mir-219a-2 in response to fibrotic stress attenuates mir-219a-5p expression and induces the up-regulation of its target gene ALDH1L2, which may reduce fibronectin deposition by suppressing PAI-1.
2023-11-01 | GSE235842 | GEO
Project description:The World Health Organization identified vitamin A deficiency (VAD) as a major public health issue in low-income communities and developing countries, while additional studies have shown dietary VAD leads to various lung pathologies. Once believed to be sterile, research now shows that transient microbial communities exist within healthy lungs and are often dysregulated in patients suffering from malnourishment, respiratory infections, and disease. The inability to parse vitamin A-mediated mechanisms from other metabolic mechanisms in humans with pathogenic endotypes, as well as the lack of data investigating how VAD affects the lung microbiome, remains a significant gap in the field. To address this unmet need, we compared molecular, metatranscriptomic, and morphometric data to identify how dietary VAD affects the lung as well as the lung microbiome. Our research shows structural and functional alterations in host-microbe-diet interactions in VAD lungs compared to vitamin A-sufficient (VAS) lungs; these changes are associated with epithelial remodeling, a breakdown in mucociliary clearance, microbial imbalance, and altered microbial colonization patterns after 8 weeks of vitamin A deficient diet. These findings confirm vitamin A is critical for lung homeostasis and provide mechanistic insights that could be valuable for the prevention of respiratory infections and disease.
2025-06-12 | GSE299530 | GEO
Project description:Vitamin A deficiencies and insufficiencies affect hundreds of millions of people in both developing and developed countries. These individuals experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared to those who are vitamin A sufficient. Previously, our laboratory has demonstrated that vitamin A-deficient (VAD) mice have significantly impaired virus-specific IgA and CD8+ T cell responses in the airways. Here we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared to control vitamin A-sufficient animals. Cytokines/chemokines that are reproducibly upregulated at the gene expression and protein levels include IFNγ and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box (Fox)P3+ T cell frequencies, we found no reduction in FoxP3+ T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that virus infection and viral antigen persistence were enhanced on day 10 post-infection in VAD animals compared to controls, and that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of virus infections in patients with VAD; efforts to enhance FoxP3+ T cell frequencies and quell immune effectors might in some cases exacerbate disease if virus has not been cleared.
2016-02-11 | GSE65805 | GEO
Project description:In response to starvation, cells undergo a metabolic shift to ensure their survival by shutting down protein synthesis and activating catabolic processes, including autophagy, to degrade proteins and recycle nutrients. These processes, however, do require protein synthesis. We asked how this fundamental conflict is resolved. Upon starvation, cells activate the Integrated Stress Response (ISR) and inhibit mammalian target of rapamycin complex 1 (mTORC1). The ISR inhibits protein translation through the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), whereas mTORC1 inhibition induces activation of the transcription factors TFEB/TFE3. We discovered that PPP1R15A (aka GADD34), a member of the protein phosphatase 1 complex (PP1) is a direct and early target of TFEB. GADD34 recruits PP1 to dephosphorylate eIF2 and thus fine-tunes protein synthesis to enable translation of the transcriptional program induced by starvation leading to a sustained autophagic flux.
2020-09-30 | PXD016149 | Pride
Project description:The objective of this study was to understand the genetic mechanisms of Vitamin-A-Deficiency (VAD)-induced arrest of spermatogonial stem-cell differentiation. Vitamin A and its derivatives (the retinoids) participate in many physiological processes including vision, cellular differentiation and reproduction. VAD affects spermatogenesis, the subject of our present study. Spermatogenesis is a highly regulated process of differentiation and complex morphologic alterations that, in the postnatal testis, leads to the formation of sperm in the seminiferous epithelium. VAD causes early cessation of spermatogenesis, characterized by degeneration of meiotic germ cells, leading to seminiferous tubules containing mostly type A spermatogonia and Sertoli cells. In this study, we investigated the molecular basis of VAD on spermatogenesis in mice. We used adult Balb/C mice fed with a Control or VAD diet for an extended period of time (8-28 weeks) and selected two time points (18 and 25 weeks) for microarray analysis. To understand the effect of VAD on the spermatogonial stem cell transcriptome, we studied isolated pure populations of spermatogonia from control and vitamin-A-deficient mice from two representative time points (18 and 25 weeks) using Affymetrix GeneChip microarrays. We identified target genes involved in the arrest of spermatogonial differentiation and spermatogenesis. Our results establish a better understanding of the chronology and magnitude of the consequences of VAD on mouse testes and add to the current knowledge of the molecular regulatory mechanisms of germ cell development.
2010-08-03 | GSE23119 | GEO
Project description:Background: Vitamin A is an essential nutrient that mammals obtain from dietary carotenoids and retinyl esters. Bile salts aid in the intestinal absorption of vitamin A, after which it is stored in the stellate cells of the liver. Vitamin A-metabolites, such as retinoic acids, are important for cell differentiation, proliferation and immunological processes, and act mostly by activating the nuclear receptors Retinoic Acid Receptor (RAR) and Retinoid Xreceptor (RXR). These receptors also perform key functions in the liver by regulating bile salt, lipid and glucose homeostasisas well is the intrahepatic immune response. Chronic liver diseases are characterized by hepatic vitamin A loss often leading to vitamin A deficiency (VAD). We found that VAD strongly aggravates liver damage in bile duct ligated (BDL) rats and in biliary atresia patients. Here, we performed a transcriptome analysis to characterize the cell biological processes in the rat liver that are disturbed in obstructive cholestasis under VADconditions. Methods: Rats were made VAD by omitting vitamin A from the diet for 16 weeks, followed by ligation of the common bile duct (BDL). 7 days later, the animals were sacrificed. During the 7 days of BDL, half of the animals received daily IP injections with retinyl-palmitate (vitamin A therapy). Bile salt concentrations and liver damage markers (AST/ALT) were determined in serum. Whole genome gene expression in liver tissue was analyzed with the Illumina platform RatRef-12 beadchip. False discovery rate (FDR) was set at a stringent 1%. Data were confirmed by quantitative real time PCR, Western blotting and/or histochemistry. Results: BDL induced dramatic liver damage in VAD rats with serum liver damage markers (AST/ALT)approximately 10-fold increased compared to BDL rats receiving a vitamin A-sufficient (VAS) diet. Only 20 genes were differentially expressed between sham-treated VAS and VAD rats and clustered in the vitamin A metabolism, immune response, carbohydrate and lipid homeostasis. In contrast, 1583 genes were differentially expressed between the BDL-treated VAS and VAD rats. The strongest effects were observed in genes from the vitamin A metabolism, immune response, collagen production and oxidative stress response. Importantly, all the liver damage markers were efficiently reversed by retinyl-palmitate therapy, which was mirrored by an almost complete normalisation of the transcript profile in VAS-BDL rats. Conclusions: We conclude that vitamin A deficiency dramatically aggravates liver damage caused by obstructive cholestasis. The transcriptome analysis suggests that a disturbed immune response may be the predominant causative factor.
2025-01-01 | GSE37313 | GEO
Project description:Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.
2023-06-19 | GSE179510 | GEO