Gene expression profile after GGPPS deletion in sertoli cell
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35755 | GEO | 2012/02/13
SECONDARY ACCESSION(S): PRJNA152099
REPOSITORIES: GEO
Similar Datasets
Project description:GGPPS was the key enzyme of mevalonate metabolic pathway which was used to synthesize the geranylgeranyl pyrophosphate (GGPP). When we deletion the GGPPS in the sertoli cell and the germ cell loss were found . We used microarrays to detail the global programme of gene expression after GGPPS deletion in sertoli cell and identified 1623 gene expression level change more than 2 times. Primary sertoli cells from 3 days old of control and KO mice for RNA extraction and hybridization on Affymetrix microarrays, every group primare sertoli cell were from more than 30 mice.
2012-02-13 | E-GEOD-35755 | biostudies-arrayexpress
Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.
2018-03-31 | E-MTAB-3263 | biostudies-arrayexpress
Project description:Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kd-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.
2020-05-12 | GSE150245 | GEO
Project description:To reveal the function of pitavastatin in cancer, we performed several experiments. In the present study, we show that pitavastatin inhibits the tumor growth through the inactivation of ERK and AKT signals by MET immaturation, and combination of pitavastatin and capmatinib, a MET inhibitor, might be useful cancer therapy in OSCC and ESCC. It could be reduced the dose of pitavastatin by using this combination therapy, resulting in decreasing the risk of adverse events such as myopathy. Taken together, the mevalonate pathway regulates the processes of MET maturation and promotes the cell growth in cancer. Moreover, the expression of GGPS1, an enzyme that synthesizes geranylgeranyl pyrophosphate (GGPP) from farnesyl pyrophosphate (FPP), associates with the sensitivity of pitavastatin, suggesting that GGPS1 could be a biomarker in cancer therapy with pitavastatin. Identification of the function of pitavastatin in oral and esophageal squamous cell carcinoma.
2021-02-19 | GSE145624 | GEO
Project description:The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR‑874 targets. Next-generation sequencing analysis revealed a significant miR-874–mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874–induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.
2022-10-03 | GSE214508 | GEO
Project description:The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR‑874 targets. Next-generation sequencing analysis revealed a significant miR-874–mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874–induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.
2022-10-03 | GSE214507 | GEO
Project description:Rationale: Geranylgeranyl pyrophosphate synthase large subunit 1 (GGPPS1), a catalase downstream of the mevalonate pathway, regulates various pathological processes through balancing the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. We sought to investigate whether GGPPS1 plays a role in mediating acute lung injury (ALI) using a mouse model of inflammation. Methods: Lipopolysaccharide (LPS) was intra-tracheally instilled to induce ALI in lung specific GGPPS1 knockout and wild-type mice. Expression of GGPPS1 in lung tissues and alveolar epithelial cells (AECs) was examined at different time points. Alveolar exudate, neutrophil infiltration, lung injury and cell death were determined. Change in global gene expression in response to GGPPS1 depletion was measured using mRNA microarray and verified in vivo and in vitro. Results: GGPPS1 levels increased significantly in lung tissues from LPS-induced ALI mice, where it showed a time- and dose-dependent increase in alveolar epithelial cells. Specific deletion of pulmonary GGPPS1 reduced the alveolar exudate and attenuated the severity of lung injury through inhibiting apoptosis of AECs. However, GGPPS1 deletion had limited effect on neutrophil counts and TNF-α levels in alveolar fluids. Deletion of GGPPS1 inhibited LPS-induced inflammasome activation, in terms of IL-1β release and pyroptosis, by down-regulating NLRP3 expression. Conclusions: Inhibition of pulmonary GGPPS1 attenuated LPS-induced ALI, predominantly by suppressing NLRP3 inflammasome activation.
2017-08-15 | GSE89311 | GEO
Project description:The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. Germ cell loss was found in Wt1 knockout mice. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. We used Digital Gene Expression Tag Profiling to detail the global programme of gene expression after Wt1 deletion in sertoli cell and identified 710 gene expression level change more than 2 times. Digital Gene Expression Tag Profiling analysis were performed using mRNA from control and Wt1-deficient Primary Sertoli cells, every group primare sertoli cell were from more than 30 mice.
2014-05-06 | E-GEOD-46664 | biostudies-arrayexpress
Project description:The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. Germ cell loss was found in Wt1 knockout mice. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. We used Digital Gene Expression Tag Profiling to detail the global programme of gene expression after Wt1 deletion in sertoli cell and identified 710 gene expression level change more than 2 times.
2014-05-06 | GSE46664 | GEO
Project description:Despite effective strategies, therapy resistance in HER2+ breast cancer remains a challenge. While the Mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Using HER2+ breast cancer parental (P) cell models (AU565, SKBR3, and UACC812), we have established anti-HER2-resistant derivatives made resistant to lapatinib (LR) or lapatinib plus trastuzumab (LTR). We performed RNA-seq on these resistant models and the P cells treated with lapatinib or lapatinib plus trastuzumaba for 24 h. We found that the average expression of the key genes in the MVA pathway, as a surrogate for pathway activity, was dramatically reduced in P cells with short-term treatment. In contrast, expression was restored or further upregulated relative to P cells in all three resistant (LR/LTR) models. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the n-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of resistant cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), but not by cholesterol. Activated YAP/TAZ and mTORC1 signaling and their downstream target gene product Survivin were inhibited by MVA blockade especially in the LR/LTR models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated S6 levels despite blockade of the MVA. The MVA may provide alternative signaling leading to cell survival and resistance when HER2 is blocked by activating YAP/TAZ-mTORC1-Survivin signaling suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy and warrant further clinical investigation.
2020-04-04 | GSE132055 | GEO