Focus on the p38 MAPK signaling pathway in bone development and maintenance.
Ontology highlight
ABSTRACT:
SUBMITTER: Thouverey C
PROVIDER: S-EPMC4461888 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Synaptic degeneration is one of the earliest pathological correlates of prion disease, and it is a major determinant of the progression of clinical symptoms. However, the cellular and molecular mechanisms underlying prion synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment of cultured hippocampal neurons with purified PrPSc, the infectious form of the prion protein, induces rapid retraction of dendritic spines, an effect that is entirely dependent on expression of endogenous PrPC by the target neurons. Here, we use this system to dissect pharmacologically the underlying cellular and molecular mechanisms. We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines. Synaptic degeneration is restricted to excitatory synapses, spares presynaptic structures, and results in decrements in functional synaptic transmission. Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration. Moreover, p38 MAPK inhibitors actually reverse the degenerative process after it has already begun. We also show that, while PrPC mediates the synaptotoxic effects of both PrPSc and the Alzheimer's Aβ peptide in this system, the two species activate distinct signaling pathways. Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases.
| S-EPMC6147624 | biostudies-literature
Project description:The objective of this study is to characterize the function of microRNA (miR)-124 in the process of coronary artery disease (CAD). Eighty patients, including 40 CAD patients and 40 non-CAD control patients were enrolled in this study. Atherosclerosis model was established in vivo in ApoE-/- mice and in vitro in RAW264.7 cells. Expression of miR-124 and p38 in patients, animal models and cell models were measured by qRT-PCR, western blot and immunohistochemistry assay. Overexpression or suppression of miR-124 was introduced in vitro and in vivo and the expression levels of p38, miR-124, pro- and anti-inflammatory cytokines, and pro- and anti-apoptotic factors were examined. Results showed that miR-124 was decreased, while p38 was increased in CAD patients and atherosclerosis models compared with control group. MiR-124 could target p38 by binding its 3' untranslated region and negatively regulated the protein expression of p38. Overexpression of miR-124 increased the expression of anti-inflammatory cytokines, reduced the expression of pro- inflammatory cytokines, and inhibited macrophage apoptosis. MiR-124 overexpression may be a promising treatment for atherosclerosis and CAD via inhibiting p38.
| S-EPMC7377888 | biostudies-literature
Project description:BackgroundBreast cancer (BRCA) is the most common cancer in women, while the bones are one of the most common sites of metastasis. Although new diagnostic methods or radiation or chemotherapies and targeted therapies have made huge advances, the occurrence of bone metastasis is also linked with poorer survival. Enhancer RNAs (eRNAs) have been demonstrated to participate in the progression of tumorigenesis and metastasis. However, the role of eRNAs in BRCA bone metastasis remains largely unclear.MethodGene expression profiling of 1,211 primary BRCA and 17 bone metastases samples were retrieved from The Cancer Genome Atlas (TCGA) database, and the significant prognostic eRNAs were identified by Cox regression and least absolute shrinkage and selection operator (LASSO) regression. The acceptable accuracy and discrimination of the nomogram were indicated by the receiver operating characteristic (ROC) and the calibration curves. Then target genes of eRNA, immune cell percentage by CIBERSORT analysis, immune genes by single-sample gene set enrichment analysis (ssGSEA), hallmark of cancer signaling pathway by gene set variation analysis (GSVA), and reverse phase protein array (RPPA) protein chip were used to build a co-expression regulation network and identified the key eRNAs in bone metastasis of BRCA. Finally, Cell Counting Kit-8 (CCK8) assay, cell cycle assay, and transwell assay were used to study changes in cell proliferation, migration, and invasiveness. Immunoprecipitation assay and Western blotting were used to test the interaction and the regulation signaling pathways.ResultsThe 27 hub eRNAs were selected, and a survival-related linear risk assessment model with a relatively high accuracy (area under curve (AUC): 0.726) was constructed. In addition, seven immune-related eRNAs (SLIT2, CLEC3B, LBPL1, FRY, RASGEF1B, DST, and ITIH5) as prognostic signatures for bone metastasis of BRCA were further confirmed by LASSO and multivariate Cox regression and CIBERSORT analysis. Finally, in vitro assay demonstrated that overexpression of SLIT2 reduced proliferation and metastasis in BRCA cells. Using high-throughput co-expression regulation network, we identified that SLIT2 may regulating P38 MAPK/c-Fos signaling pathway to promote the effects of metastasis.ConclusionBased on the co-expression network for bone metastasis of BRCA, we screened key eRNAs to explore a prognostic model in predicting the bone metastasis by bioinformatics analysis. Besides, we identified the potential regulatory signaling pathway of SLIT2 in BRCA bone metastasis, which provides a promising therapeutic strategy for metastasis of BRCA.
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Project description:Purpose:Retinoblastoma is a malignant tumor of the developing retina that mostly occurs in children. Our study aimed to investigate the effect of tripartite motif-containing protein 59 (TRIM59) on retinoblastoma growth and the underlying mechanisms. Methods:We performed bioinformatic analysis of three datasets (GSE24673, GSE97508, and GSE110811) from the Gene Expression Omnibus database. Quantitative reverse-transcription PCR and immunoblotting of three retinoblastoma cell lines were conducted to verify TRIM59 as a differentially expressed gene. Specific siRNAs were used to inhibit TRIM59 expression in the HXO-Rb44 cell line. A lentiviral vector was transfected into the Y79 cell line to overexpress TRIM59. The effects of TRIM59 on retinoblastoma cell proliferation, cell cycling, and apoptosis were explored in vitro using the abovementioned cell lines. The effect of TRIM59 expression on retinoblastoma cell proliferation was evaluated in a mouse xenograft tumor model. Results:TRIM59 expression in three retinoblastoma cell lines was remarkably elevated compared with normal control. Knocking down TRIM59 expression remarkably suppressed cell proliferation and growth and promoted cell apoptosis in HXO-Rb44 cells, whereas TRIM59 overexpression promoted tumor progression in Y79 cells. Silencing TRIM59 also markedly inhibited in vivo tumor growth in the xenograft model. Mechanistic studies revealed that TRIM59 upregulated phosphorylated p38, p-JNK1/2, p-ERK1/2, and p-c-JUN expression in retinoblastoma cells. Notably, the p38 inhibitor SB203580 attenuated the effects of TRIM59 on cell proliferation, apoptosis, and the G1/S phase transition. Conclusions:TRIM59 plays an oncogenic role in retinoblastoma and exerts its tumor-promotive function by activating the p38-mitogen-activated protein kinase pathway.
| S-EPMC7441337 | biostudies-literature
Project description:BackgroundThe dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear.MethodsWe exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype.ResultsWe found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression.ConclusionsOur results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.
| S-EPMC9178829 | biostudies-literature
Project description:Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38beta and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38beta agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.
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Project description:S100A11 is reported to associate with progression and poor prognosis in several tumors. We previously reported that S100A11 was highly expressed in intrahepatic cholangiocarcinoma (ICC) cells and promoted TGF-β1-induced EMT through SMAD2/3 signaling pathway. Here, we explored the prognostic role of S100A11 on ICC patients and preliminary molecular mechanisms how S100A11 regulated ICC cell proliferation. Our results showed that S100A11 was obviously increased in ICC tumor tissues. High expression of S100A11 was closely correlated with lymph node metastasis (LNM) and TNM stage and was an independent risk factor for patients' overall survival (OS) and recurrence-free survival (RFS). The nomograms comprising LNM and S100A11 achieved better predictive accuracy compared with TNM staging system for OS and RFS prediction. Silencing S100A11 significantly suppressed RBE cells and HCCC9810 cells proliferation, colony formation, and activation of P38/mitogen-activated protein kinase (MAPK) signaling pathway in vitro and inhibited tumor growth in vivo. In contrast, the overexpression of S100A11 in RBE cells and HCCC9810 cells achieved the opposite results. S100A11-induced proliferation was abolished after treatment with P38 inhibitor. Our findings suggest S100A11/P38/MAPK signaling pathway may be a potential therapeutic target for ICC patients.
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Project description:BackgroundOvarian cancer is the most lethal gynecology malignancy in the world, therefore, research on the molecular biological mechanism of ovarian cancer tumorigenesis and progression has received widespread attention.MethodsWe identified RPS6KA2 as the prognosis-related gene of ovarian cancer from TCGA, GSE26712 and GSE26193 database via bioinformatic analysis. qRT-PCR and western blot detected the differential expression of RPS6KA2 in normal ovaries and ovarian cancer tissues. The biological functions of RPS6KA2 were verified by in vitro and in vivo. GSEA analysis was used to select candidate signaling pathway of RPS6KA2 which was further verified by western blot. The possible binding sites of RPS6KA2 with miRNAs and circRNAs were predicted by bioinformatics analysis, and then a circRNA-miRNA-mRNA interaction network was constructed.ResultsWe found the expression of RPS6KA2 was down-regulated in ovarian cancer tissues. Overexpression of RPS6KA2 could suppress cell proliferation, whereas knockdown of RPS6KA2 had the opposite effects on proliferation. GSEA analysis showed that the MARK signaling pathway was closely associated with RPS6KA2. Bioinformatics analysis and dual-luciferase reporter assay showed that RPS6KA2 was regulated with miR-19a-3p, miR-106a-5p and miR-519d-3p. Further analysis showed that circFAM169A was the common ceRNA of miR-19a-3p, miR-106a-5p and miR-519d-3p. Dual-luciferase reporter assay showed the relationship of circFAM169A and miR-106a-5p and miR-519d-3p. After network analysis, one circRNA-miRNA-mRNA axis (circFAM169A/miR-106a-5p, miR-519d-3p/RPS6KA2) was identified.ConclusionsWe demonstrated that circFAM169A/miR-106a-5p, miR-519d-3p mediated low expression of RPS6KA2 could affect the proliferation of ovarian cancer cells via p38/MAPK signaling pathway.
| S-EPMC9893488 | biostudies-literature
Project description:The circadian clock regulates various physiological processes, including bone metabolism. The nuclear receptors Reverbs, comprising Rev-erb? and Rev-erb?, play a key role as transcriptional regulators of the circadian clock. In this study, we demonstrate that Rev-erbs negatively regulate differentiation of osteoclasts and osteoblasts. The knockdown of Rev-erb? in osteoclast precursor cells enhanced receptor activator of nuclear factor-?B ligand (RANKL)-induced osteoclast formation, as well as expression of nuclear factor of activated T cells 1 (NFATc1), osteoclast-associated receptor (OSCAR), and tartrate-resistant acid phosphatase (TRAP). The overexpression of Rev-erb? leads to attenuation of the NFATc1 expression via inhibition of recruitment of c-Fos to the NFATc1 promoter. The overexpression of Rev-erb? in osteoblast precursors attenuated the expression of osteoblast marker genes including Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OC). Rev-erb? interfered with the recruitment of Runx2 to the promoter region of the target genes. Conversely, knockdown of Reverb? in the osteoblast precursors enhanced the osteoblast differentiation and function. In addition, Rev-erb? negatively regulated osteoclast and osteoblast differentiation by suppressing the p38 MAPK pathway. Furthermore, intraperitoneal administration of GSK4112, a Rev-erb agonist, protects RANKL-induced bone loss via inhibition of osteoclast differentiation in vivo . Taken together, our results demonstrate a molecular mechanism of Rev-erbs in the bone remodeling, and provide a molecular basis for a potential therapeutic target for treatment of bone disease characterized by excessive bone resorption.
| S-EPMC6999712 | biostudies-literature
Project description:We investigated the potential protective effect of rutinum (RUT) against pirarubicin- (THP-) induced cardiotoxicity. THP was used to induce toxicity in rat H9c2 cardiomyoblasts. Positive control cells were pretreated with a cardioprotective agent dexrazoxane (DZR) prior to treatment with THP. Some of the cells were preincubated with RUT and a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, both individually and in combination, prior to THP exposure. At a dose range of 30-70 μM, RUT significantly prevented THP-induced reduction in cell viability; the best cardioprotective effect was observed at a dose of 50 μM. Administration of RUT and SB203580, both individually as well as in combination, suppressed the elevation of intracellular ROS, inhibited cell apoptosis, and reversed the THP-induced upregulation of TGF-β1, p-p38 MAPK, cleaved Caspase-9, Caspase-7, and Caspase-3. A synergistic effect was observed on coadministration of RUT and SB203580. RUT protected against THP-induced cardiotoxicity by inhibition of ROS generation and suppression of cell apoptosis. The cardioprotective effect of RUT appears to be associated with the modulation of the TGF-β1-p38 MAPK signaling pathway.
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