8 results on '"myocardin related transcription factor"'
Search Results
2. Cell Type Dependent Suppression of Inflammatory Mediators by Myocardin Related Transcription Factors
- Author
-
Li Liu, Elisabeth Bankell, Catarina Rippe, Björn Morén, Karin G. Stenkula, Bengt-Olof Nilsson, and Karl Swärd
- Subjects
cytokines ,inflammation ,atherosclerosis ,human coronary artery ,myocardin related transcription factor ,differentiation ,Physiology ,QP1-981 - Abstract
Myocardin related transcription factors (MRTFs: MYOCD/myocardin, MRTF-A, and MRTF-B) play a key role in smooth muscle cell differentiation by activating contractile genes. In atherosclerosis, MRTF levels change, and most notable is a fall of MYOCD. Previous work described anti-inflammatory properties of MRTF-A and MYOCD, occurring through RelA binding, suggesting that MYOCD reduction could contribute to vascular inflammation. Recent studies have muddled this picture showing that MRTFs may show both anti- and pro-inflammatory properties, but the basis of these discrepancies remain unclear. Moreover, the impact of MRTFs on inflammatory signaling pathways in tissues relevant to human arterial disease is uncertain. The current work aimed to address these issues. RNA-sequencing after forced expression of myocardin in human coronary artery smooth muscle cells (hCASMCs) showed reduction of pro-inflammatory transcripts, including CCL2, CXCL8, IL6, and IL1B. Side-by-side comparison of MYOCD, MRTF-A, and MRTF-B in hCASMCs, showed that the anti-inflammatory impact was shared among MRTFs. Correlation analyses using human arterial transcriptomic datasets revealed negative correlations between MYOCD, MRTFA, and SRF, on the one hand, and the inflammatory transcripts, on the other. A pro-inflammatory drive from lipopolysaccharide, did not change the size of the suppressive effect of MRTF-A in hCASMCs on either mRNA or protein levels. To examine cell type-dependence, we compared the anti-inflammatory impact in hCASMCs, with that in human bladder SMCs, in endothelial cells, and in monocytes (THP-1 cells). Surprisingly, little anti-inflammatory activity was seen in endothelial cells and monocytes, and in bladder SMCs, MRTF-A was pro-inflammatory. CXCL8, IL6, and IL1B were increased by the MRTF-SRF inhibitor CCG-1423 and by MRTF-A silencing in hCASMCs, but depolymerization of actin, known to inhibit MRTF activity, had no stimulatory effect, an exception being IL1B. Co-immunoprecipitation supported binding of MRTF-A to RelA, supporting sequestration of this important pro-inflammatory mediator as a mechanism. Dexamethasone treatment and silencing of RelA (by 76 ± 1%) however only eliminated a fraction of the MRTF-A effect (≈25%), suggesting mechanisms beyond RelA binding. Indeed, SRF silencing suggested that MRTF-A suppression of IL1B and CXCL8 depends on SRF. This work thus supports an anti-inflammatory impact of MRTF-SRF signaling in hCASMCs and in intact human arteries, but not in several other cell types. more...
- Published
- 2021
- Full Text
- View/download PDF
Catalog
3. Cell Type Dependent Suppression of Inflammatory Mediators by Myocardin Related Transcription Factors.
- Author
-
Liu, Li, Bankell, Elisabeth, Rippe, Catarina, Morén, Björn, Stenkula, Karin G., Nilsson, Bengt-Olof, and Swärd, Karl
- Subjects
INFLAMMATORY mediators ,TRANSCRIPTION factors ,CELLULAR signal transduction ,MUSCLE cells ,CONTRACTILE proteins ,ARTERIAL diseases ,ATHEROSCLEROSIS ,BLADDER cancer - Abstract
Myocardin related transcription factors (MRTFs: MYOCD/myocardin, MRTF-A, and MRTF-B) play a key role in smooth muscle cell differentiation by activating contractile genes. In atherosclerosis, MRTF levels change, and most notable is a fall of MYOCD. Previous work described anti-inflammatory properties of MRTF-A and MYOCD, occurring through RelA binding, suggesting that MYOCD reduction could contribute to vascular inflammation. Recent studies have muddled this picture showing that MRTFs may show both anti- and pro-inflammatory properties, but the basis of these discrepancies remain unclear. Moreover, the impact of MRTFs on inflammatory signaling pathways in tissues relevant to human arterial disease is uncertain. The current work aimed to address these issues. RNA-sequencing after forced expression of myocardin in human coronary artery smooth muscle cells (hCASMCs) showed reduction of pro-inflammatory transcripts, including CCL2 , CXCL8 , IL6 , and IL1B. Side-by-side comparison of MYOCD, MRTF-A, and MRTF-B in hCASMCs, showed that the anti-inflammatory impact was shared among MRTFs. Correlation analyses using human arterial transcriptomic datasets revealed negative correlations between MYOCD , MRTFA , and SRF , on the one hand, and the inflammatory transcripts, on the other. A pro-inflammatory drive from lipopolysaccharide, did not change the size of the suppressive effect of MRTF-A in hCASMCs on either mRNA or protein levels. To examine cell type-dependence, we compared the anti-inflammatory impact in hCASMCs, with that in human bladder SMCs, in endothelial cells, and in monocytes (THP-1 cells). Surprisingly, little anti-inflammatory activity was seen in endothelial cells and monocytes, and in bladder SMCs, MRTF-A was pro-inflammatory. CXCL8 , IL6 , and IL1B were increased by the MRTF-SRF inhibitor CCG-1423 and by MRTF-A silencing in hCASMCs, but depolymerization of actin, known to inhibit MRTF activity, had no stimulatory effect, an exception being IL1B. Co-immunoprecipitation supported binding of MRTF-A to RelA, supporting sequestration of this important pro-inflammatory mediator as a mechanism. Dexamethasone treatment and silencing of RelA (by 76 ± 1%) however only eliminated a fraction of the MRTF-A effect (≈25%), suggesting mechanisms beyond RelA binding. Indeed, SRF silencing suggested that MRTF-A suppression of IL1B and CXCL8 depends on SRF. This work thus supports an anti-inflammatory impact of MRTF-SRF signaling in hCASMCs and in intact human arteries, but not in several other cell types. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
- Full Text
- View/download PDF
4. Cell Type Dependent Suppression of Inflammatory Mediators by Myocardin Related Transcription Factors
- Author
-
Catarina Rippe, Björn Morén, Karl Swärd, Elisabeth Bankell, Bengt-Olof Nilsson, Karin G. Stenkula, and Li Liu
- Subjects
Cell type ,Physiology ,Smooth muscle cell differentiation ,Inflammation ,differentiation ,CCL2 ,Biology ,cytokines ,Cell biology ,human coronary artery ,Myocardin ,inflammation ,Physiology (medical) ,medicine ,Gene silencing ,myocardin related transcription factor ,QP1-981 ,Signal transduction ,medicine.symptom ,atherosclerosis ,Transcription factor ,Original Research - Abstract
Myocardin related transcription factors (MRTFs: MYOCD/myocardin, MRTF-A, and MRTF-B) play a key role in smooth muscle cell differentiation by activating contractile genes. In atherosclerosis, MRTF levels change, and most notable is a fall of MYOCD. Previous work described anti-inflammatory properties of MRTF-A and MYOCD, occurring through RelA binding, suggesting that MYOCD reduction could contribute to vascular inflammation. Recent studies have muddled this picture showing that MRTFs may show both anti- and pro-inflammatory properties, but the basis of these discrepancies remain unclear. Moreover, the impact of MRTFs on inflammatory signaling pathways in tissues relevant to human arterial disease is uncertain. The current work aimed to address these issues. RNA-sequencing after forced expression of myocardin in human coronary artery smooth muscle cells (hCASMCs) showed reduction of pro-inflammatory transcripts, including CCL2, CXCL8, IL6, and IL1B. Side-by-side comparison of MYOCD, MRTF-A, and MRTF-B in hCASMCs, showed that the anti-inflammatory impact was shared among MRTFs. Correlation analyses using human arterial transcriptomic datasets revealed negative correlations between MYOCD, MRTFA, and SRF, on the one hand, and the inflammatory transcripts, on the other. A pro-inflammatory drive from lipopolysaccharide, did not change the size of the suppressive effect of MRTF-A in hCASMCs on either mRNA or protein levels. To examine cell type-dependence, we compared the anti-inflammatory impact in hCASMCs, with that in human bladder SMCs, in endothelial cells, and in monocytes (THP-1 cells). Surprisingly, little anti-inflammatory activity was seen in endothelial cells and monocytes, and in bladder SMCs, MRTF-A was pro-inflammatory. CXCL8, IL6, and IL1B were increased by the MRTF-SRF inhibitor CCG-1423 and by MRTF-A silencing in hCASMCs, but depolymerization of actin, known to inhibit MRTF activity, had no stimulatory effect, an exception being IL1B. Co-immunoprecipitation supported binding of MRTF-A to RelA, supporting sequestration of this important pro-inflammatory mediator as a mechanism. Dexamethasone treatment and silencing of RelA (by 76 ± 1%) however only eliminated a fraction of the MRTF-A effect (≈25%), suggesting mechanisms beyond RelA binding. Indeed, SRF silencing suggested that MRTF-A suppression of IL1B and CXCL8 depends on SRF. This work thus supports an anti-inflammatory impact of MRTF-SRF signaling in hCASMCs and in intact human arteries, but not in several other cell types. more...
- Published
- 2021
- Full Text
- View/download PDF
5. Expression of type I collagen and tenascin C is regulated by actin polymerization through MRTF in dedifferentiated chondrocytes.
- Author
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Parreno, Justin, Raju, Sneha, Niaki, Mortah Nabavi, Andrejevic, Katarina, Jiang, Amy, Delve, Elizabeth, and Kandel, Rita
- Subjects
- *
TENASCIN , *ACTIN , *POLYMERIZATION , *MYOCARDIN , *CARTILAGE cells , *FIBROBLASTS , *GENE expression , *GENETIC transcription - Abstract
This study examined actin regulation of fibroblast matrix genes in dedifferentiated chondrocytes. We demonstrated that dedifferentiated chondrocytes exhibit increased actin polymerization, nuclear localization of myocardin related transcription factor (MRTF), increased type I collagen (col1) and tenascin C (Tnc) gene expression, and decreased Sox9 gene expression. Induction of actin depolymerization by latrunculin treatment or cell rounding, reduced MRTF nuclear localization, repressed col1 and Tnc expression, and increased Sox9 gene expression in dedifferentiated chondrocytes. Treatment of passaged chondrocytes with MRTF inhibitor repressed col1 and Tnc expression, but did not affect Sox9 expression. Our results show that actin polymerization regulates fibroblast matrix gene expression through MRTF in passaged chondrocytes. [ABSTRACT FROM AUTHOR] more...
- Published
- 2014
- Full Text
- View/download PDF
6. Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer.
- Author
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Tello-Lafoz, Maria, Srpan, Katja, Sanchez, Elisa E., Hu, Jing, Remsik, Jan, Romin, Yevgeniy, Calò, Annalisa, Hoen, Douglas, Bhanot, Umeshkumar, Morris, Luc, Boire, Adrienne, Hsu, Katharine C., Massagué, Joan, Huse, Morgan, and Er, Ekrem Emrah more...
- Subjects
- *
MELANOMA , *KILLER cells , *LYMPHOCYTES , *CYTOTOXIC T cells , *CANCER cells , *CELL migration - Abstract
Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment with immune checkpoint blockade (ICB) antibodies. We also observed that high MRTF signaling in human melanoma is associated with ICB efficacy in patients. Using biophysical and functional assays, we showed that MRTF overexpression rigidified the filamentous actin cytoskeleton and that this mechanical change rendered mouse and human cancer cells more vulnerable to cytotoxic T lymphocytes and natural killer cells. Collectively, these results suggest that immunosurveillance has a mechanical dimension, which we call mechanosurveillance, that is particularly relevant for the targeting of metastatic disease. • Metastatic cells with high MRTF activity are vulnerable to cytotoxic lymphocytes in vivo • Strong MRTF signaling is associated with responsiveness to immune checkpoint blockade • Cancer cells overexpressing MRTF induce stronger lymphocyte activation and cytotoxicity • MRTF makes cancer cells more stimulatory to lymphocytes by increasing their rigidity [Display omitted] Myocardin-related transcription factors promote metastatic colonization by inducing cell spreading and migration. Tello-Lafoz et al. show that the cellular stiffening that accompanies this morphologic change triggers a mechanical form of immunosurveillance in which cytotoxic lymphocytes destroy the metastatic cells. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
- Full Text
- View/download PDF
7. Expression of type I collagen and tenascin C is regulated by actin polymerization through MRTF in dedifferentiated chondrocytes
- Author
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Elizabeth Delve, Sneha Raju, Justin Parreno, Rita A. Kandel, Amy Jiang, Katarina Andrejevic, and Mortah Nabavi Niaki
- Subjects
Myocardin related transcription factor ,Biophysics ,Active Transport, Cell Nucleus ,macromolecular substances ,Biochemistry ,Chondrocyte ,Collagen Type I ,Polymerization ,Chondrocytes ,Structural Biology ,Gene expression ,Tenascin C ,Genetics ,medicine ,Animals ,Anilides ,Fibroblast ,Molecular Biology ,Actin ,Cell Nucleus ,biology ,Chemistry ,Tenascin ,Cell Biology ,Cell Dedifferentiation ,musculoskeletal system ,Bridged Bicyclo Compounds, Heterocyclic ,Molecular biology ,Actins ,medicine.anatomical_structure ,Myocardin ,embryonic structures ,Benzamides ,biology.protein ,Latrunculin ,Thiazolidines ,Cattle ,Dedifferentiation ,Collagen ,Type I collagen ,Transcription Factors - Abstract
This study examined actin regulation of fibroblast matrix genes in dedifferentiated chondrocytes. We demonstrated that dedifferentiated chondrocytes exhibit increased actin polymerization, nuclear localization of myocardin related transcription factor (MRTF), increased type I collagen (col1) and tenascin C (Tnc) gene expression, and decreased Sox9 gene expression. Induction of actin depolymerization by latrunculin treatment or cell rounding, reduced MRTF nuclear localization, repressed col1 and Tnc expression, and increased Sox9 gene expression in dedifferentiated chondrocytes. Treatment of passaged chondrocytes with MRTF inhibitor repressed col1 and Tnc expression, but did not affect Sox9 expression. Our results show that actin polymerization regulates fibroblast matrix gene expression through MRTF in passaged chondrocytes. more...
- Published
- 2014
8. A-kinase anchoring protein-Lbc promotes pro-fibrotic signaling in cardiac fibroblasts.
- Author
-
Cavin S, Maric D, and Diviani D
- Subjects
- Actins metabolism, Angiotensin II pharmacology, Animals, Cell Differentiation drug effects, Cell Movement drug effects, Collagen biosynthesis, Enzyme Activation drug effects, Fibroblasts drug effects, Fibrosis, GTP-Binding Protein alpha Subunits, G12-G13 metabolism, Gene Silencing drug effects, Minor Histocompatibility Antigens, Models, Biological, Myofibroblasts drug effects, Myofibroblasts pathology, Phenotype, Rats, Transforming Growth Factor beta1 metabolism, Up-Regulation drug effects, rhoA GTP-Binding Protein metabolism, A Kinase Anchor Proteins metabolism, Fibroblasts metabolism, Fibroblasts pathology, Heart Ventricles pathology, Signal Transduction drug effects
- Abstract
In response to stress or injury the heart undergoes an adverse remodeling process associated with cardiomyocyte hypertrophy and fibrosis. Transformation of cardiac fibroblasts to myofibroblasts is a crucial event initiating the fibrotic process. Cardiac myofibroblasts invade the myocardium and secrete excess amounts of extracellular matrix proteins, which cause myocardial stiffening, cardiac dysfunctions and progression to heart failure. While several studies indicate that the small GTPase RhoA can promote profibrotic responses, the exchange factors that modulate its activity in cardiac fibroblasts are yet to be identified. In the present study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor (GEF) activity, is critical for activating RhoA and transducing profibrotic signals downstream of type I angiotensin II receptors (AT1Rs) in cardiac fibroblasts. In particular, our results indicate that suppression of AKAP-Lbc expression by infecting adult rat ventricular fibroblasts with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly reduces the ability of angiotensin II to promote RhoA activation, differentiation of cardiac fibroblasts to myofibroblasts, collagen deposition as well as myofibroblast migration. Interestingly, AT1Rs promote AKAP-Lbc activation via a pathway that requires the α subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as a key Rho-guanine nucleotide exchange factor modulating profibrotic responses in cardiac fibroblasts., (Copyright © 2013 Elsevier B.V. All rights reserved.) more...
- Published
- 2014
- Full Text
- View/download PDF
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