Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Endothelin-1 driven proliferation of PASMC is c-fos dependent

ABSTRACT: Background: Pulmonary hypertension is a rare disease characterized by pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascularremodeling. Multiple factors have been associated with the vessel wall thickening. However, the responsible mechanisms are not fully understood. Aim: In this study we aim to decipher the role ofc-fos and c-jun transcription factors in the vascular remodeling process. Methods and Results: Expression and immunohistochemical analyses revealed high expression of c-fos and c-jun transcription factors in the vessel wall of lungs from human IPAH samples, hypoxia exposed mice and monocrotaline treated rats. Microarray study from hypoxic lung homogenates revealed MAP kinase asthe most differentially regulated pathway. Additionally, ET-1 and CTGF were the most up-regulated genes. Consequently, ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferative markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated ERK-dependent c-fos expression and phosphorylation of c-fos and c-jun. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMC. Conclusion: This finding shed light on the involvement of c-fos/c-jun in vascular remodeling as well as on the molecular mechanisms regulating the proliferative response of PASMCs to ET-1. 36 mice were divided into 2 groups and kept either under normoxic (Nox) or under hypoxic conditions (Hox.3h). RNA from 3 animals was pooled to get 6 pools per group. Each pool was subjected to microarray hybridization (Nox vs. Hox.3h) in a balanced dye-swap design, giving a total of 6 dual-color hybridizations.

ORGANISM(S): Mus musculus

SUBMITTER: Jochen Wilhelm

PROVIDER: E-GEOD-56698 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Endothelin-1 driven proliferation of PASMC is c-fos dependent

Project description:Background: Pulmonary hypertension is a rare disease characterized by pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascularremodeling. Multiple factors have been associated with the vessel wall thickening. However, the responsible mechanisms are not fully understood. Aim: In this study we aim to decipher the role ofc-fos and c-jun transcription factors in the vascular remodeling process. Methods and Results: Expression and immunohistochemical analyses revealed high expression of c-fos and c-jun transcription factors in the vessel wall of lungs from human IPAH samples, hypoxia exposed mice and monocrotaline treated rats. Microarray study from hypoxic lung homogenates revealed MAP kinase asthe most differentially regulated pathway. Additionally, ET-1 and CTGF were the most up-regulated genes. Consequently, ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferative markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated ERK-dependent c-fos expression and phosphorylation of c-fos and c-jun. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMC. Conclusion: This finding shed light on the involvement of c-fos/c-jun in vascular remodeling as well as on the molecular mechanisms regulating the proliferative response of PASMCs to ET-1.

2014-04-11 | GSE56698 | GEO

Differential Gene Expression Profiles of PASMCs Induced by Quercetin under Hypoxia

Project description:As the critical step of pathogenesis during hypoxic pulmonary arterial hypertension (PAH) vascular remodeling is closely associated with pulmonary arterial smooth muscle cell (PASMC) alterations induced by hypoxia that include persistent vasoconstriction, abnormal proliferation and PASMC resistance to apoptosis. Quercetin is a flavonoid compound extracted from green plants that inhibits proliferation, induces apoptosis, arrests the cell cycle, and rescues the constriction of PASMCs, but the underlying mechanisms remain poorly understood. In this study, we used a commercial Agilent Whole Rat Genome Oligo Microarray to determine the overall transcriptional response of PASMCs in response to exposure to hypoxia and the optimal concentration of quercetin. Hypoxia induced the upregulation of 1694 genes and the downregulation of 2091 genes compared with the normoxia group. Quercetin treatment resulted in 1790 upregulated genes and 1450 downregulated genes. Quercetin is known to cause differential expression of several of these genes that are known to promote proliferation, induce apoptosis (Cycs, Ppp3ca, Prkar2b, Akt3, Ppp3cc, Il1rap, Ntrk1), arrest the cell cycle (Chek2, Cdkn1c, Gadd45b, Stag2, Anapc7, Orc1, Ccne1, Myc3, Skp1, Espl1, Cdc45, Mcm4), and rescue PASMC constriction (Ramp1, Ramp3, Adcy5, Gnas, Prkcd, Itpr3, Adra1d, Calm1, Npr1, Avpr1a, Ednra, Adcy8). Real-time quantitative RT-PCR was performed to verify the microarray results. In conclusion, quercetin altered the expression profile of many genes regulated by hypoxia in PASMCs, which helps to further explore the mechanism of the effects of quercetin treatment on hypoxic PAH.

2015-08-20 | GSE72181 | GEO

Endothelial senescence mediates hypoxia-induced vascular remodeling by modulating PDGFB expression

Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. The levels of senescence marker, p16INK4A and senescence-associated β-galactosidase (SA-β-gal) activity are higher in PA endothelial cells (ECs) isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16fl/fl-Cdh5(PAC)-CreERT2 (p16iΔEC) mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing platelet-derived growth factor (PDGFB) expression. Transcriptomic analyses of IPAH patient or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and their interaction with TWIST1. Knockdown of p16INK4A attenuates the expression of PDGFB and TWIST1 in IPAH patient PAECs or hypoxia-treated mouse lungs and suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel implanted on the mouse lungs. Hypoxia-treated mouse lung EC-derived exosomes stimulate DNA synthesis and migration of PASMCs in vitro and in the gel implanted on the mouse lungs, while p16iΔEC mouse lung EC-derived exosomes inhibit the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.

2022-10-15 | PXD033549 | Pride

Implication of EZH2 in the hyper-proliferative and apoptosis-resistant phenotype of pulmonary artery smooth muscle cells in PAH: a transcriptomic and proteomic approach

Project description:The aim of this study was to determine whether EZH2 represents a new factor critically involved in the cancer-like phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and TCA cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.

2021-04-14 | GSE166996 | GEO

c-Fos mediates cell proliferation, invasion and drug-resistance of lung adenocarcinoma through MAPK signal pathway

Project description:Lung cancer is the main cause of cancer-related death in men and women all over the world. Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, with the overall 5-year survival rate is less than 20% . We found the mRNA expression of c-Fos in LUAD clinical samples was decreased significantly compared to adjacent normal control. Overexpression of c-Fos inhibited LUAD cell proliferation, colony formation, and induced cell apoptosis while c-Fos knockdown promoted cell proliferation, colony formation, and suppressed cell apoptosis. Cell cycle showed little difference after c-Fos knockdown but overexpression of c-Fos increased the distribution of G1 phase when decreased G2 phase cells. Knockdown of c-Fos reduced the sensitivity of LUAD cells to cisplatin but overexpression of c-Fos increased the efficacy of cisplatin both in vitro and in vivo. MAPK signaling pathway was enriched after c-Fos was overexpressed in LUAD cells. The expression of c-Jun, c-Myc and DUSP1 was greatly inhibited after c-Fos overexpression but incresed after c-Fos knockdown, which suggests c-Fos regulated MAPK signaling pathway in LUAD. Furthermore, c-Fos was shown to interact with c-Jun and overexpression of c-Jun partially recovered the expression of c-Jun, c-Myc and DUSP1 caused by c-Fos overexpression. Cell proliferation was also rescued when apoptosis was decreased followed by c-Jun overexpression. In contrast, knockdown of c-Jun inhibited cell proliferation and promoted cell apoptosis in LUAD cells when reduced the level of c-Jun, c-Myc and DUSP1. In summary, c-Fos inhibits cell proliferation, promotes apoptosis and increses cisplatin-sensitivity of lung adenocarcinoma cells via regulating MAPK signaling by interacting with c-Jun in certain LUADs.

2023-09-20 | GSE213590 | GEO

Mus musculus

Project description:Endothelin-1 driven proliferation of PASMC is c-fos dependent

| PRJNA244323 | ENA

Effect of FOS and JUN expression in inmortalized human mesenchymal progenitor cells

Project description:Mesenchymal progenitor cells (MPCs) have been proposed as cells of origin for sarcomas, while c-Fos and c-Jun transcription factors have been proposed has a oncogenes in sarcoma tumors. Here we study the effects of the induction of c-fos or c-Jun expression in immortalized hMPCs. C-Fos expression in these cells not only generated modifications in cell cycle, but also morphological changes, reduced mobility capacity and impaired adipogenic and osteogenic differentiation potentials. Even more interesting, c-Fos expressing immortalized hMPCs generated tumors with chondrogenic phenotype when implanted in immunodeficient mice. In accordance with these results, c-Fos is expressed at protein level in many human bone tumors, specifically in chondrosarcomas (76% c-fos positive samples) and osteosarcomas (49% c-fos positive samples). c-Jun expression in immortalized hMPCs induces increased proliferation and cell transformation and, once implanted in immunodeficient mice, these cells generate fibroblastic osteosarcomas. Doble c-jun and c-fos expression in immortalized hMPCs also induces cell transformation and yields high grade pleomorphic osteosarcoma tumors when implanted in immunodeficient mice.

2018-07-17 | GSE79158 | GEO

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.

2013-09-19 | E-GEOD-47898 | biostudies-arrayexpress

A non-canonical repressor function of JUN restrains YAP activity and suppresses YAP-dependent liver cancer growth [3prime_Seq_JUNoe]

Project description:The transcriptional coactivators YAP/TAZ are the critical downstream regulators of the Hippo pathway that regulate gene expression in response to changes in pathway activity, mainly by binding to TEAD transcription factors. Uncontrolled transcriptional output of YAP/TAZ can lead to rapid induction of aggressive tumor growth. AP-1 is a dimeric basic leucine zipper (bZIP) transcription factor complex with JUN and FOS proteins being the most abundant members of this family. Unlike FOS, JUN can also form homodimers, but in the cell, JUN presumably preferentially forms heterodimers with members of the FOS family, which act as potent transcriptional activators. Previous studies identified substantial co-occupancy of YAP/TAZ and AP-1 at genomic sites, and they demonstrated that JUN/FOS heterodimers cooperate with the YAP/TAZ and TEAD transcription factors to drive YAP/TAZ target gene expression. Here, we now elucidate a negative feedback mechanism in which high YAP activity is restrained by the recruitment of homodimeric JUN::JUN/NCOR1 repressor complexes and show that this noncanonical JUN function is part of a tumor suppressor mechanism in the liver.

2024-06-30 | GSE235613 | GEO