scholarly journals Transcriptomic Profiling of DAF-7/TGFβ Pathway Mutants in C. elegans

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 288
Author(s):  
Muhan Hu ◽  
David Crossman ◽  
Jeevan K. Prasain ◽  
Michael A. Miller ◽  
Rosa A. Serra
Keyword(s):  
Gene Ontology ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Differentially Expressed ◽  
Gene Ontology Analysis ◽  
Wild Type ◽  
C Elegans ◽  
Growth Factor Beta ◽  
Tgfβ Pathway

The transforming growth factor beta superfamily encompasses a large family of ligands that are well conserved across many organisms. They are regulators of a number of physiological and pathological processes. The model nematode Caenorhabditis elegans has been instrumental in identifying key components of the transforming growth factor beta (TGFβ) pathway. In C. elegans, the TGFβ homolog DAF-7 signals through the DAF-1 Type I and DAF-4 Type II receptors to phosphorylate downstream R-SMADs DAF-8 and DAF-14. These R-SMADs translocate into the nucleus to inhibit Co-SMAD DAF-3. Many of the roles of the canonical DAF-7 pathway, involving both DAF-1 and DAF-3, have been identified using targeted genetic studies. Few have assessed the global transcriptomic changes in response to these genes, especially in adult animals. In this study, we performed RNA sequencing on wild type, daf-1, and daf-1; daf-3 adult hermaphrodites. To assess the overall trends of the data, we identified differentially expressed genes (DEGs) and performed gene ontology analysis to identify the types of downstream genes that are differentially expressed. Hierarchical clustering showed that the daf-1; daf-3 double mutants are transcriptionally more similar to wild type than daf-1 mutants. Analysis of the DEGs showed a disproportionally high number of genes whose expression is increased in daf-1 mutants, suggesting that DAF-1 acts as a general repressor of gene expression in wild type animals. Gene ontology analysis of the DEGs produced many significantly enriched terms, including Molting Cycle, Response to Topologically Incorrect Protein, and Response to Biotic Stimulus. Understanding the direct and indirect targets of the DAF-7 TGFβ pathway through this RNA-seq dataset can provide insight into novel roles of the multifunctional signaling pathway, as well as identify novel genes that may participate in previously reported functions of TGFβ signaling.

Association between genetic variations in transforming growth factor beta pathway and overall survival in patients with non-small cell lung cancer treated with definitive radiotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17530-e17530
Author(s):  
Weili Wang ◽  
Kerby A Shedden ◽  
Feng-Ming (Spring) Kong
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Definitive Radiotherapy ◽  
Growth Factor Beta ◽  
Tgfβ Pathway

e17530 Background: The transforming growth factor beta (TGFβ) pathway, an important regulator in cellular metabolic process, has been reported for significant association with cancer prognosis. This study was to exam the association between single nucleotide polymorphisms (SNPs) of TGFβ pathway and overall survival (OS) in subjects with non-small cell lung cancer (NSCLC). Methods: Patients with stage I-III NSCLC received definitive radiotherapy with/without chemotherapy were eligible to this prospective study. The primary endpoint was OS which was calculated from radiation treatment start to death or censored. DNA samples for genotyping were extracted from buffy-coat which was collected before commencement of treatment. 19 SNPs in 10 genes (BMP1, BMP2, INHBC, SMAD1, SMAD3, SMAD4, SMAD6, SMAD7, SMAD8, TGFβ1), which was reported to have significant correlation with OS of lung cancer, were selected. MassArray System (Sequenom Company) was used for genotyping. Cox regression was performed for multivariate analysis to examine the effects of genotypes on OS using dominant and recessive genetic model. Results: 126 consecutive patients, 91% of them were Caucasian, were recruited in this study. All SNPs call rates were over 90%. Assay reproducibility was over 99% by random double-blinding duplicate or triplicate genotyping. Among clinical factors analyzed, radiation dose was only significant independent factor predicting OS (P=0.001). Genotypic association study showed that 7 SNPs (rs235756, rs11939979, rs12102171, rs6494633, rs12456284, rs12906898 and rs4803455) were significantly associated with OS, adjusted for age, gender, smoking, histology, clinical stage, tumor volume, Karnofsky Performance Status, radiotherapy dose, and chemotherapy. The strongest association was in SMAD3: rs12102171 (P=0.004, HR=2.28, 95%CI, 1.26-4.15). Conclusions: This study partly validated findings from previous studies that genetic variations in the TGFβ pathway are significant predictors of overall survival in NSCLC patients treated with definitive radiotherapy with/without chemotherapy.

scholarly journals Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 14 (8) ◽  
pp. 798
Author(s):  
Carlos Pascual-Morena ◽  
Iván Cavero-Redondo ◽  
Alicia Saz-Lara ◽  
Irene Sequí-Domínguez ◽  
Maribel Lucerón-Lucas-Torres ◽  
...  
Keyword(s):  
Systematic Review ◽  
Duchenne Muscular Dystrophy ◽  
Growth Factor ◽  
Muscular Dystrophy ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Growth Factor Beta ◽  
Meta Analyses ◽  
Tgfβ Pathway

The transforming growth factor beta (TGFβ) pathway could modulate the Duchenne muscular dystrophy (DMD) phenotype. This meta-analysis aims to estimate the association of genetic variants involved in the TGFβ pathway, including the latent transforming growth factor beta binding protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP1) genes, among others, with age of loss of ambulation (LoA) and cardiac function in patients with DMD. Meta-analyses were conducted for the hazard ratio (HR) of LoA for each genetic variant. A subgroup analysis was performed in patients treated exclusively with glucocorticoids. Eight studies were included in the systematic review and four in the meta-analyses. The systematic review suggests a protective effect of LTBP4 haplotype IAAM (recessive model) for LoA. It is also suggested that the SPP1 rs28357094 genotype G (dominant model) is associated with early LoA in glucocorticoids-treated patients. The meta-analysis of the LTBP4 haplotype IAAM showed a protective association with LoA, with an HR = 0.78 (95% CI: 0.67–0.90). No association with LoA was observed for the SPP1 rs28357094. The LTBP4 haplotype IAAM is associated with a later LoA, especially in the Caucasian population, while the SPP1 rs28357094 genotype G could be associated with a poor response to glucocorticoids. Future research is suggested for SPP1 rs11730582, LTBP4 rs710160, and THBS1 rs2725797.

Abstract 41: Postnatal Deletion of Vascular Smooth Muscle Cell Transforming Growth Factor beta Receptor 2 in Mice Exacerbates Marfan-syndrome-associated Aortic Dilation

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hao Wei ◽  
Stoyan N Angelov ◽  
Jie Hong Hu ◽  
David A Dichek
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Intramural Hematoma ◽  
Ascending Aorta ◽  
Wild Type ◽  
Aortic Pathology ◽  
Growth Factor Beta

Objectives: Thoracic aortic aneurysms (TAA) are an important cause of cardiovascular death and are often part of an autosomal dominant syndrome (e.g., Marfan syndrome; MFS). The role of transforming growth factor beta (TGF-β) signaling in TAA is controversial. Excessive TGF-β signaling in aortic smooth muscle cells (SMC) is proposed to cause TAA formation; however, much data support a protective role for aortic SMC TGF-β signaling. We investigated the role of SMC TGF-β signaling in the development of MFS-associated TAA by superimposing SMC-specific deletion of Tgfbr2 on MFS-related aortic pathology of Fbn1 C1039G/+ mice. Methods: We crossed Tgfbr2 flox/flox mice with Acta2 -CreERT2 mice (Tamoxifen-inducible Cre driven by the SMC-specific Acta 2 promoter) to generate mice with inducible deletion of Tgfbr 2 in SMCs. 4 groups of mice were studied: 1) Fbn1 +/+ , Acta2 -CreERT2 o/o , Tgfbr2 flox/flox mice received Tamoxifen (wild-type control); 2) Fbn1 C1039G /+ , Acta2 -CreERT2 o/o , Tgfbr2 flox/flox mice received Tamoxifen (MFS; controlled for Tamoxifen); 3) Fbn1 C1039G /+ , Acta2 -CreERT2 +/o , Tgfbr2 flox/flox mice received vehicle (MFS; controlled for Acta2 -CreERT2 +/o ); 4) Fbn1 C1039G /+ , Acta2 -CreERT2 +/o , Tgfbr2 flox/flox mice received Tamoxifen (SMC- Tgfbr2 -/- superimposed on MFS). All mice received Tamoxifen or vehicle at 6 wk of age; ascending aortic anatomy was assessed at 16 wk of age. Results: Compared to wild-type mice, both groups of MFS mice had significantly increased ascending aortic diameter (~30%; p<0.05; ANOVA). Both groups of mice with MFS alone (Tamoxifen- and Acta2 -CreERT2 +/o -controls) showed comparable ascending aorta dilation and similar prevalence of aortic intramural hematoma. Superimposing the SMC- Tgfbr2 -/- genotype on the Fbn1 C1039G /+ genotype mice further increased both ascending aorta diameter (>40%; p<0.05; ANOVA) and intramural hematoma rate (~4-fold; p<0.05, X ° test) compared to mice with MFS alone. Studies are under way to delineate the alterations of vascular SMC TGF-β signaling in these models. Conclusions: Our data suggest that loss of TGF-β signaling in vascular SMC exacerbates aortic pathology in MFS mice and that vascular SMC TGF-β signaling protects against TAA formation induced by fibrillin deficiency.

Application of Laser Capture Microdissection to Craniofacial Biology: Characterization of Anatomically Relevant Gene Expression in Normal and Craniosynostotic Rabbit Sutures

2017 ◽  
Vol 54 (1) ◽  
pp. 109-118 ◽  
Author(s):  
S. Alex Rottgers ◽  
Phillip Gallo ◽  
James Gilbert ◽  
Zoe Macisaac ◽  
James Cray ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Morphogenetic Protein ◽  
Growth Factor Beta ◽  
Laser Capture ◽  
Regional Gene

Objective Fusion of the cranial sutures is thought to depend on signaling among perisutural tissues. Mapping regional variations in gene expression would improve current models of craniosynostosis. Laser capture microdissection (LCM) isolates discrete cell populations for gene expression analysis. LCM has rarely been used in the study of mineralized tissue. This study sought to evaluate the potential use of LCM for mapping of regional gene expression within the cranial suture. Design Coronal sutures were isolated from 10-day-old wild-type and craniosynostotic (CS) New Zealand White rabbits, and LCM was used to isolate RNA from the sutural ligament (SL), osteogenic fronts (OF), dura mater, and periosteum. Relative expression levels for Fibroblast Growth Factor 2 (FGF2), Fibroblast Growth Factor Receptor 2 (FGFR2), Transforming Growth Factor Beta 2 (TGFβ-2), Transforming Growth Factor Beta 3 (TGFβ-3), Bone Morphogenetic Protein 2 (BMP-2), Bone Morphogenetic Protein 4 (BMP-4), and Noggin were determined using quantitative real-time PCR. Results A fivefold increase in TGFβ2 expression was detected in the CS SL relative to wild type, whereas 152-fold less TGFβ-3 was detected within the OF of CS animals. Noggin expression was increased by 10-fold within the CS SL, but reduced by 13-fold within the CS dura. Reduced expression of FGF2 was observed within the CS SL and dura, whereas increased expression of FGFR2 was observed within the CS SL. Reduced expression of BMP-2 was observed in the CS periosteum, and elevated expression of BMP-4 was observed in the CS SL and dura. Conclusions LCM provides an effective tool for measuring regional variations in cranial suture gene expression. More precise measurements of regional gene expression with LCM may facilitate efforts to correlate gene expression with suture morphogenesis and pathophysiology.

scholarly journals Disruption of transforming growth factor beta signaling by a mutation that prevents transphosphorylation within the receptor complex.

1995 ◽  
Vol 15 (3) ◽  
pp. 1573-1581 ◽  
Author(s):  
J Cárcamo ◽  
A Zentella ◽  
J Massagué
Keyword(s):  
Growth Factor ◽  
Ligand Binding ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Signal Propagation ◽  
Tgf Beta ◽  
Wild Type ◽  
Growth Factor Beta ◽  
Signaling Activity

T beta R-II (transforming growth factor beta [TGF-beta] type II receptor) is a transmembrane serine/threonine kinase that acts as the primary TGF-beta receptor. Ligand binding to T beta R-II leads to the recruitment and phosphorylation of T beta R-I, a distantly related transmembrane kinase that acts as a downstream signaling component. T beta R-I phosphorylation by T beta R-II is shown here to be essential for signaling. A mutant T beta R-II that binds ligand but lacks signaling activity was identified. This mutant was identified by screening with a TGF-beta-inducible vector a series of mink lung epithelial cell clones that have normal TGF-beta binding activity but have lost antiproliferative and transcriptional responses to TGF-beta. When transiently cotransfected with T beta R-II, one of these cell lines, S-21, recovered TGF-beta responsiveness. cDNA cloning and sequencing of T beta R-II from S-21 cells revealed a point mutation that changes proline 525 to leucine in kinase subdomain XI. A recombinant receptor containing this mutation, T beta R-II(P525L), is similar to wild-type T beta R-II in its abilities to bind ligand, support ligand binding to T beta R-I, and form a complex with T beta R-I in vivo. T beta R-II(P525L) has autophosphorylating activity in vitro and in vivo; however, unlike the wild-type receptor, it fails to phosphorylate an associated T beta R-I. These results suggest that T beta R-II(P525L) is a catalytically active receptor that cannot recognize T beta R-I as a substrate. The close link between T beta R-I transphosphorylation and signaling activity argues that transphosphorylation is essential for signal propagation via T beta R-I.

scholarly journals Differential expression of transforming growth factor beta receptor 2 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Differential Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Normal Breast ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Beta Receptor ◽  
Growth Factor Beta

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding transforming growth factor beta receptor 2, TGFBR2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. TGFBR2 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of TGFBR2 in primary tumors of the breast was correlated with recurrence-free survival in patients with HER2+ subtype cancers, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. TGFBR2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals MO011PODOCYTE NEPHRONECTIN IS REGULATED BY TRANSFORMING GROWTH FACTOR BETA VIA THE CANONICAL AND NON-CANONICAL PATHWAYS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Nina Sopel ◽  
Alexandra Ohs ◽  
Mario Schiffer ◽  
Janina Müller-Deile
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Protein Level ◽  
Transforming Growth Factor ◽  
Canonical Pathways ◽  
Growth Factor Beta ◽  
Tgfβ Pathway ◽  
Different Parts

Abstract Background and Aims The glomerular basement membrane (GBM), podocytes and glomerular endothelial cells (GEC) are composing the glomerular filtration barrier (GFB) within the glomerulus. Both podocytes and GEC are essential components for the synthesis of the extracellular matrix (ECM) of the GBM. One ECM protein of the GBM, which is mainly produced by podocytes is nephronectin (NPNT). An altered expression pattern of NPNT has been observed in different kidney diseases. While NPNT was shown to be down regulated in membranous glomerulonephropathy, its expression was elevated in diabetic glomerulopathy, compared to healthy controls. Using a morpholino-induced knockdown of npnt in zebrafish larvae, proteinuria, podocyte foot process effacement and thickening of the lamia rara interna of the GBM were observed. Mice that were intra peritoneally injected with a microRNA 378a (miR-378a) mimic showed a decrease in NPNT expression in the kidneys on both mRNA and protein level, suggesting a regulatory effect of miR-378a on NPNT. In addition, in cultured human podocytes treatment with transforming growth factor beta (TGFβ), as well as transfection with miR-378a mimic down regulated NPNT mRNA and protein expression. By blocking different parts of the TGFβ pathway, we want to further investigate the mechanisms by which TGFβ mediates the regulation of NPNT in podocytes. Method Our main model for this study are immortalized human podocytes, which are proliferating at 33°C and differentiating at 37°C due to a temperature sensitive SV40 large T antigen. Ten to 12 days differentiated podocytes were used for experiments. Differentiated cells were either transfected with a miR-192 or control miR mimic or pre-incubated with different inhibitors for components of both the canonical and the non-canonical TGFβ signaling pathways, followed by culture with or without additional TGFβ. Cell lysates were prepared to be used for Western Blot or qPCR analyses. Results Treatment of immortalized human podocytes with TGFβ decreased NPNT expression on mRNA and protein level. After transfecting immortalized human podocytes with a miR-192 mimic, a GEC-derived miR up regulated by TGFβ stimulation, we observed reduced NPNT expression, compared to control miR transfection. Blocking TGFβ receptor I signaling with the specific inhibitor SD208, caused higher NPNT protein abundance, while NPNT mRNA expression remained unchanged. Targeting downstream parts of both the canonical and non-canonical TGFβ pathways by using inhibitors for single molecules of the respective arms of the intricate TGFβ pathway showed ambiguous results. Suppression of either Smad2 and/or Smad3 tended to enhance NPNT protein levels, accompanied by mostly unaltered mRNA expression. Blockade of different parts of the non-canonical TGFβ pathway also up regulated protein expression of NPNT. However, NPNT mRNA expression was more variable. Therefore, regulation of podocyte NPNT might not be due to changes in mRNA transcription, but to modifications on posttranscriptional level. Conclusion Treating immortalized human podocytes with TGFβ or TGFβ-induced miR-192 reduced NPNT expression on both the mRNA and protein level. More detailed analysis with inhibition of different parts of the canonical and non-canonical TGFβ pathways hint that both pathways are involved in NPNT expression. Therefore, we suggest that the regulation of podocyte NPNT by TGFβ is fine-tuned via both the canonical and non-canonical pathways with additional modulation through TGFβ dependent miRs.

scholarly journals Transforming growth factor beta signaling in hepatocellular carcinoma: as a victim or culprit?

2019 ◽  
Vol 6 (3) ◽  
pp. 991
Author(s):  
Varun Kumar Sharma ◽  
Charu Tyagi ◽  
Yugandhar P. Reddy ◽  
Jayanand Manjhi ◽  
Lomas Kumar Tomar
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Signalling Pathway ◽  
Expression Of Genes ◽  
Tgfβ Signalling ◽  
Growth Factor Beta ◽  
Tgfβ Pathway

The transforming growth factor-β (TGFβ) signalling pathway control various cellular function and play a pivotal role in tumour suppression. In contrary, overexpression of TGFβ is linked to promote the cancer development. TGFβ facilitate cell-growth and cell-differentiation process which support tumour propagation. In case of hepatocellular carcinoma (HCC), TGFβ signalling pathway is the master regulator of HCCs pathogenesis and functionally involved in the regulation of HCCs phenotype via modulating the downstream signalling pathways. In this article, we have highlighted the contradictory behaviour of TGFβ in hepatocellular carcinoma. Observations suggest that the TGFβ signalling pathway is positively correlated to the expression of genes linked with various hepatic pathological conditions, including fibrosis, cirrhosis, inflammation and cancer. TGFβ pathway play dual role as pro and anti-tumoural activities in cancer cells depending on their context.

scholarly journals A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma.

1996 ◽  
Vol 16 (7) ◽  
pp. 3480-3489 ◽  
Author(s):  
P I Knaus ◽  
D Lindemann ◽  
J F DeCoteau ◽  
R Perlman ◽  
H Yankelev ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cell Lymphoma ◽  
Tumor Development ◽  
Cutaneous T Cell Lymphoma ◽  
Tgf Beta ◽  
Wild Type ◽  
Growth Factor Beta

In many cancers, inactivating mutations in both alleles of the transforming growth factor beta (TGF-beta) type 11 receptor (TbetaRII) gene occur and correlate with loss of sensitivity to TGF-beta. Here we describe a novel mechanism for loss of sensitivity to growth inhibition by TGF-beta in tumor development. Mac-1 cells, isolated from the blood of a patient with an indolent form of cutaneous T-cell lymphoma, express wild-type TbetaRII and are sensitive to TGF-beta. Mac-2A cells, clonally related to Mac-1 and isolated from a skin nodule of the same patient at a later, clinically aggressive stage of lymphoma, are resistant to TGF-beta. They express both the wild-type TbetaRII and a receptor with a single point mutation (Asp-404-Gly [D404G]) in the kinase domain (D404G-->TbetaRII); no TbetaRI or TbetaRII is found on the plasma membrane, suggesting that D404G-TbetaRII dominantly inhibits the function of the wild-type receptor by inhibiting its appearance on the plasma membrane. Indeed, inducible expression, under control of a tetracycline-regulated promoter, of D404G-TbetaRII in TGF-beta- sensitive Mac-1 cells as well as in Hep3B hepatoma cells results in resistance to TGF-beta and disappearance of cell surface TbetaRI and TbetaRII. Overexpression of wild-type TbetaRII in Mac-2A cells restores cell surface TbetaRI and TbetaRH and sensitivity to TGF-beta. The ability of the D404G-TbetaRH to dominantly inhibit function of wild-type TGF-beta receptors represents a new mechanism for loss of sensitivity to the growth-inhibitory functions of TGF-beta in tumor development.

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