PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1093124 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28491650.fastq.gz | Fastqsanger.gz | |||
| SRR28491651.fastq.gz | Fastqsanger.gz | |||
| SRR28491652.fastq.gz | Fastqsanger.gz | |||
| SRR28491653.fastq.gz | Fastqsanger.gz | |||
| SRR28491654.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Bladder cancer, one of the most diagnosed cancers worldwide, is associated with high morbidity, mortality, and a poor prognosis. The PIN1 phospho-dependent prolyl isomerase is frequently overexpressed in many human cancer types and affects tumor initiation and progression through disrupting the balance of oncoprotein and tumor suppressor protein signaling. However, the functional pSer/Thr.Pro protein substrates of PIN1 and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we discovered that ablation of Pin1 in human/mouse bladder cancer cells and organoids formed from mouse primary urothelial cells resulted in decreased cell proliferation, stemness maintenance, cell invasion, migration, urothelium clearance capacity, and reduced free/total cholesterol levels in vitro. Re-expressing Pin1 in Pin1 knockout cells reversed the defects caused by lack of Pin1. Moreover, in vivo subcutaneous xenograft and allograft transplantation mouse models combined with an orthotopic implantation model were utilized to confirm a positive role for Pin1 in controlling tumor growth and potential metastasis. Therapeutically, a combination of the sulfopin PIN1 inhibitor and the simvastatin HMGCR inhibitor was shown to suppress cell proliferation in vitro and tumor growth in vivo synergistically. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways in PIN1 knockout cells via RNA-sequencing and used a suite of diverse molecular and biochemical approaches to show that PIN1 interacts with JNK-dependent phosphorylated SREBP2 (Ser455) and vice versa. These results indicate that active cholesterol biosynthesis pathway in bladder cancer cells is regulated by PIN1-mediated isomerization and JNK-mediated phosphorylation of its key transcriptional factor SREBP2. These findings emphasize that PIN1 can act as a regulator and potential therapeutic target in bladder cancer.
2024-11-17 | GSE262761 | GEO
Project description:In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2
2023-10-06 | GSE196294 | GEO
Project description:This RNA-Seq analysis compares gene expression of the peptidyl-prolyl isomerase Pin1 mutant pin1∆ contrasting to the WT in the fission yeast S. pombe
2020-03-20 | GSE144092 | GEO
Project description:Metabolic reprogramming is well-appreciated to be able to control macrophage activation. However, it remains unknown whether the SREBPs-lipogenesis pathway is involved in macrophage alternative (or M2) activation. Here, we showed that IL4-induced M2 activation was coupled with increased SREBP2 maturation and activated cholesterol biosynthetic pathway, while the SREBP1-fatty acid biosynthesis pathway remained unaffected after IL4 stimulation. Genetic or pharmacologic blockade of SREBP2 maturation significantly inhibited IL4-induced M2 activation independent of cholesterol. Instead, cholesterol inhibited M2 activation most likely through its feedback regulation of SREBP2 maturation. Mechanically, the upregulation of SREBP2 maturation was dependent on the activation of upstream MTOR, and mature SREBP2 increased the expression of KAZALD1 and subsequently activated the IGF1 signaling to promote IL4-induced M2 activation. Consistently, myeloid-specific Scap deficiency markedly decreased the number of M2 macrophages in the lung and attenuated the HDM-induced allergic airway inflammation. Taken together, these findings highlight a critical role for cholesterol homeostatic regulator SREBP2 in M2 activation, which advances our understanding of the regulation of immunometabolism for M2 activation and points to new opportunities for therapeutic control of M2 activation and allergic airway inflammation.
2023-04-30 | GSE188356 | GEO
Project description:Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.
2024-04-07 | GSE208160 | GEO
Project description:Carbon dioxide regulates cholesterol levels through SREBP2
| PRJNA804192 | ENA
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked to altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity and hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-06-01 | GSE169712 | GEO
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-09-10 | GSE183790 | GEO
Project description:There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes, however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and its master regulator, SREBP2, in the EC responses to inflammatory stress. Treatment of ECs with pro-inflammatory cytokines upregulates SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-kB DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-kB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC.
2022-04-28 | GSE201466 | GEO
Project description:Pin1 is a prolyl isomerase that plays an important role in cancer, Alzheimer's disease, and asthma. To understand how Pin1 levels affect mRNA abundance on a genome-wide scale, we knocked down Pin1 by siRNA and used microarray-based gene expression profiling to identify candidate genes that are significantly up- or down-regulated by Pin1 siRNA. The data provide important information on Pin1-responsive genes. We find that genes that are inherently unstable and have short half-lives are targeted by Pin1.
2012-10-27 | GSE41868 | GEO