scholarly journals Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-β

2008 ◽  
Vol 295 (5) ◽  
pp. F1303-F1312 ◽  
Author(s):  
Pál Pacher ◽  
Kumar Sharma ◽  
György Csordás ◽  
Yanqing Zhu ◽  
György Hajnóczky
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Complications ◽  
Transforming Growth Factor Β ◽  
Sole Source ◽  
Atp Production ◽  
Permeabilized Cells ◽  
Cellular Processes ◽  
Diabetic Vascular Complications ◽  
Key Factor

Transforming growth factor-β (TGF-β) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-β alters cytosolic [Ca2+] ([Ca2+]c) signals, which in some cases may result from the downregulation of the IP3 receptor Ca2+ channels (IP3R). Ca2+ released by IP3Rs is effectively transferred from endoplasmic reticulum (ER) to the mitochondria to stimulate ATP production and to allow feedback control of the Ca2+ mobilization. To assess the effect of TGF-β on the ER-mitochondrial Ca2+ transfer, we first studied the [Ca2+]c and mitochondrial matrix Ca2+ ([Ca2+]m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-β pretreatment (24 h) decreased both the [Ca2+]c and [Ca2+]m responses evoked by angiotensin II or endothelin. Strikingly, the [Ca2+]m signal was more depressed than the [Ca2+]c signal and was delayed. In permeabilized cells, TGF-β pretreatment attenuated the rate but not the magnitude of the IP3-induced [Ca2+]c rise, yet caused massive depression of the [Ca2+]m responses. ER Ca2+ storage and mitochondrial uptake of added Ca2+ were not affected by TGF-β. Also, TGF-β had no effect on mitochondrial distribution and on the ER-mitochondrial contacts assessed by two-photon NAD(P)H imaging and electron microscopy. Downregulation of both IP3R1 and IP3R3 was found in TGF-β-treated PGASMC. Thus, TGF-β causes uncoupling of mitochondria from the ER Ca2+ release. The sole source of this would be suppression of the IP3R-mediated Ca2+ efflux, indicating that the ER-mitochondrial Ca2+ transfer depends on the maximal rate of Ca2+ release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophysiology associated with TGF-β production.

scholarly journals Modulation of the TGF-β signaling pathway by long noncoding RNA in hepatocellular carcinoma

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Mengzhen Han ◽  
Zhibin Liao ◽  
Furong Liu ◽  
Xiaoping Chen ◽  
Bixiang Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Therapy Targets ◽  
Non Coding Rnas

AbstractHepatocellular carcinoma (HCC) is a type of liver cancer with poor prognosis. There have been demonstrated to exist many possible mechanisms in HCC tumorigenesis, and recent investigations have provided some promising therapy targets. However, further mechanisms remain to be researched to improve the therapeutic strategy and diagnosis of HCC. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which plays critical roles in networks of different cellular processes, and TGF-β signaling has been found to participate in tumor initiation and development of HCC in recent years. Moreover, among the molecules and signaling pathways, researchers paid more attention to lncRNAs (long non-coding RNAs), but the connection between lncRNAs and TGF-βremain poorly understood. In this review, we conclude the malignant procedure which lncRNAs and TGF-β involved in, and summarize the mechanisms of lncRNAs and TGF-βin HCC initiation and development. Furthermore, the interaction between lncRNA and TGF-β are paid more attention, and the potential therapy targets are mentioned.

scholarly journals Role of transforming growth factor-β in hematologic malignancies

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4589-4596 ◽  
Author(s):  
Mei Dong ◽  
Gerard C. Blobe
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Myeloproliferative Disorders ◽  
Transforming Growth Factor Β ◽  
Hematologic Malignancies ◽  
Negative Regulator ◽  
Cellular Processes ◽  
Signaling Field

AbstractThe transforming growth factor-β (TGF-β) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-β signaling pathway is a potent negative regulator of proliferation while stimulating differentiation and apoptosis when appropriate. In hematologic malignancies, including leukemias, myeloproliferative disorders, lymphomas, and multiple myeloma, resistance to these homeostatic effects of TGF-β develops. Mechanisms for this resistance include mutation or deletion of members of the TGF-β signaling pathway and disruption of the pathway by oncoproteins. These alterations define a tumor suppressor role for the TGF-β pathway in human hematologic malignancies. On the other hand, elevated levels of TGF-β can promote myelofibrosis and the pathogenesis of some hematologic malignancies through their effects on the stroma and immune system. Advances in the TGF-β signaling field should enable targeting of the TGF-β signaling pathway for the treatment of hematologic malignancies.

scholarly journals Molecular and Cellular Mechanisms of Palate Development

2017 ◽  
Vol 96 (11) ◽  
pp. 1184-1191 ◽  
Author(s):  
C. Li ◽  
Y. Lan ◽  
R. Jiang
Keyword(s):  
Growth Factor ◽  
Regulatory Networks ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Mechanisms ◽  
Palate Development ◽  
Palatal Shelf ◽  
Cellular Processes ◽  
Morphogenetic Protein ◽  
Secondary Palate

Development of the mammalian secondary palate involves highly dynamic morphogenetic processes, including outgrowth of palatal shelves from the oral side of the embryonic maxillary prominences, elevation of the initially vertically oriented palatal shelves to the horizontal position above the embryonic tongue, and subsequently adhesion and fusion of the paired palatal shelves at the midline to separate the oral cavity from the nasal cavity. Perturbation of any of these processes could cause cleft palate, a common birth defect that significantly affects patients’ quality of life even after surgical treatment. In addition to identifying a large number of genes required for palate development, recent studies have begun to unravel the extensive cross-regulation of multiple signaling pathways, including Sonic hedgehog, bone morphogenetic protein, fibroblast growth factor, transforming growth factor β, and Wnt signaling, and multiple transcription factors during palatal shelf growth and patterning. Multiple studies also provide new insights into the gene regulatory networks and/or dynamic cellular processes underlying palatal shelf elevation, adhesion, and fusion. Here we summarize major recent advances and integrate the genes and molecular pathways with the cellular and morphogenetic processes of palatal shelf growth, patterning, elevation, adhesion, and fusion.

scholarly journals The structural basis of TGF-β, bone morphogenetic protein, and activin ligand binding

Reproduction ◽  
2006 ◽  
Vol 132 (2) ◽  
pp. 179-190 ◽  
Author(s):  
S Jack Lin ◽  
Thomas F Lerch ◽  
Robert W Cook ◽  
Theodore S Jardetzky ◽  
Teresa K Woodruff
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Structural Basis ◽  
Cellular Processes ◽  
Morphogenetic Protein ◽  
Check Points ◽  
Membrane Level

The transforming growth factor-β (TGF-β) superfamily is a large group of structurally related growth factors that play prominent roles in a variety of cellular processes. The importance and prevalence of TGF-β signaling are also reflected by the complex network of check points that exist along the signaling pathway, including a number of extracellular antagonists and membrane-level signaling modulators. Recently, a number of important TGF-β crystal structures have emerged and given us an unprecedented clarity on several aspects of the signal transduction process. This review will highlight these latest advances and present our current understanding on the mechanisms of specificity and regulation on TGF-β signaling outside the cell.

scholarly journals Cell-specificity of transforming growth factor-β response is dictated by receptor bioavailability

2006 ◽  
Vol 36 (3) ◽  
pp. 591-600 ◽  
Author(s):  
Magdalena I Suszko ◽  
Teresa K Woodruff
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Reproductive Function ◽  
Transforming Growth Factor Β ◽  
Family Control ◽  
Cellular Processes ◽  
Relative Contribution ◽  
A Cell ◽  
Mouse Pituitary ◽  
And Migration

Members of the transforming growth factor-β (TGFβ) family control diverse cellular responses including differentiation, proliferation, controlled cell death and migration. The response of a cell to an individual ligand is highly restricted yet the signaling pathways for TGFβ, activin and bone morphogenic proteins share a limited number of receptors and activate similar intracellular cytoplasmic co-regulators, Smads. A central question in the study of this family of ligands is how cells titrate and integrate each TGFβ-like signal in order to respond in a cell- and ligand-specific manner. This study uses the pituitary gonadotrope cell line, LβT2, as a model to delineate the relative contribution of TGFβ and activin ligands to follicle-stimulating hormone (FSH) biosynthesis. It was found that pituitary gonadotrope cells do not express the TGFβ type II (TβRII) receptor and are therefore not responsive to the TGFβ ligand. Transfection of the receptor restores TGFβ signaling capabilities and the TGFβ-mediated stimulation of FSHβ gene transcription in LβT2 cells. Consequently, we evaluated the presence of the TβRII in the adult mouse pituitary. TβRII does not co-localize with FSH-producing cells; however it is detected on the cell surface of prolactin- and growth hormone-positive cells. Taken together, these results suggest that the bioavailability of the TGFβ-specific receptor rather than TGFβ dictates pituitary gonadotrope selectivity to activin, which is necessary to maintain normal reproductive function. It is likely that the ligand-restricted mechanisms employed by the gonadotrope are present in other cells, which could explain the distinct control of many cellular processes by members of the TGFβ superfamily.

scholarly journals Structural insights into conformational switching in latency-associated peptide between transforming growth factor β-1 bound and unbound states

IUCrJ ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 238-252
Author(s):  
Timothy R. Stachowski ◽  
Mary E. Snell ◽  
Edward H. Snell
Keyword(s):  
Growth Factor ◽  
Conformational Change ◽  
Large Scale ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Binding Motif ◽  
Conformational Switching ◽  
Cellular Processes ◽  
Therapeutic Development ◽  
Endogenous Activity

Transforming growth factor β-1 (TGFβ-1) is a secreted signalling protein that directs many cellular processes and is an attractive target for the treatment of several diseases. The primary endogenous activity regulatory mechanism for TGFβ-1 is sequestration by its pro-peptide, latency-associated peptide (LAP), which sterically prohibits receptor binding by caging TGFβ-1. As such, recombinant LAP is promising as a protein-based therapeutic for modulating TGFβ-1 activity; however, the mechanism of binding is incompletely understood. Comparison of the crystal structure of unbound LAP (solved here to 3.5 Å resolution) with that of the bound complex shows that LAP is in a more open and extended conformation when unbound to TGFβ-1. Analysis suggests a mechanism of binding TGFβ-1 through a large-scale conformational change that includes contraction of the inter-monomer interface and caging by the `straight-jacket' domain that may occur in partnership through a loop-to-helix transition in the core jelly-roll fold. This conformational change does not appear to include a repositioning of the integrin-binding motif as previously proposed. X-ray scattering-based modelling supports this mechanism and reveals possible orientations and ensembles in solution. Although native LAP is heavily glycosylated, solution scattering experiments show that the overall folding and flexibility of unbound LAP are not influenced by glycan modification. The combination of crystallography, solution scattering and biochemical experiments reported here provide insight into the mechanism of LAP sequestration of TGFβ-1 that is of fundamental importance for therapeutic development.

scholarly journals Role of Transforming Growth Factor-β in Skeletal Muscle Fibrosis: A Review

2019 ◽  
Vol 20 (10) ◽  
pp. 2446 ◽  
Author(s):  
Ahmed Ismaeel ◽  
Jeong-Su Kim ◽  
Jeffrey S. Kirk ◽  
Robert S. Smith ◽  
William T. Bohannon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Muscle Fibrosis ◽  
Cellular Processes ◽  
Targeted Treatments ◽  
Skeletal Muscle Fibrosis

Transforming growth factor-beta (TGF-β) isoforms are cytokines involved in a variety of cellular processes, including myofiber repair and regulation of connective tissue formation. Activation of the TGF-β pathway contributes to pathologic fibrosis in most organs. Here, we have focused on examining the evidence demonstrating the involvement of TGF-β in the fibrosis of skeletal muscle particularly. The TGF-β pathway plays a role in different skeletal muscle myopathies, and TGF-β signaling is highly induced in these diseases. In this review, we discuss different molecular mechanisms of TGF-β-mediated skeletal muscle fibrosis and highlight different TGF-β-targeted treatments that target these relevant pathways.

scholarly journals Transforming Growth Factor-β Induces Nuclear Import of Smad3 in an Importin-β1 and Ran-dependent Manner

2001 ◽  
Vol 12 (4) ◽  
pp. 1079-1091 ◽  
Author(s):  
Akira Kurisaki ◽  
Shingo Kose ◽  
Yoshihiro Yoneda ◽  
Carl-Henrik Heldin ◽  
Aristidis Moustakas
Keyword(s):  
Growth Factor ◽  
Nuclear Import ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Structural Basis ◽  
Type I ◽  
Dependent Manner ◽  
Permeabilized Cells ◽  
Terminal Domain

Smad proteins are cytoplasmic signaling effectors of transforming growth factor-β (TGF-β) family cytokines and regulate gene transcription in the nucleus. Receptor-activated Smads (R-Smads) become phosphorylated by the TGF-β type I receptor. Rapid and precise transport of R-Smads to the nucleus is of crucial importance for signal transduction. By focusing on the R-Smad Smad3 we demonstrate that 1) only activated Smad3 efficiently enters the nucleus of permeabilized cells in an energy- and cytosol-dependent manner. 2) Smad3, via its N-terminal domain, interacts specifically with importin-β1 and only after activation by receptor. In contrast, the unique insert of exon3 in the N-terminal domain of Smad2 prevents its association with importin-β1. 3) Nuclear import of Smad3 in vivo requires the action of the Ran GTPase, which mediates release of Smad3 from the complex with importin-β1. 4) Importin-β1, Ran, and p10/NTF2 are sufficient to mediate import of activated Smad3. The data describe a pathway whereby Smad3 phosphorylation by the TGF-β receptor leads to enhanced interaction with importin-β1 and Ran-dependent import and release into the nucleus. The import mechanism of Smad3 shows distinct features from that of the related Smad2 and the structural basis for this difference maps to the divergent sequences of their N-terminal domains.

Perianale Fisteln bei CED: vom Mausmodell zur Klinik

2018 ◽  
Vol 75 (5) ◽  
pp. 287-294
Author(s):  
Michael Scharl
Keyword(s):  
Growth Factor ◽  
Morbus Crohn ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 13

Zusammenfassung. Fisteln stellen nach wie vor eine der wichtigsten Komplikationen bei Patienten mit Morbus Crohn dar. Bei mindestens einem Drittel aller Morbus Crohn Patienten treten im Laufe der Erkrankung Fisteln auf. Eine dauerhafte Heilung der Fistel wird jedoch, auch unter Ausschöpfung sämtlicher medikamentöser und chirurgischer Therapieoptionen, nur in rund einem Drittel dieser Patienten erreicht. Der genaue molekulare Mechanismus der Fistelentstehung ist bis heute nicht ganz klar. Aus histopathologischer Sichtweise stellen Fisteln eine röhrenartige Struktur dar, welche von flachen epithelartigen Zellen ausgekleidet ist. Als ursächlicher Entstehungsmechanismus wird dabei die sogenannte epitheliale-zu-mesenchymale Transition (EMT) angesehen und es kann eine starke Expression der Entzündungsmediatoren Tumor Nekrose Faktor, Interleukin-13 und Transforming Growth Factor β in den Fistelarealen nachgewiesen werden. Zusätzlich zu den bereits etablierten, medikamentösen Therapieoptionen, also Antibiotika, Immunmodulatoren und anti-TNF Antikörper, stellt insbesondere der Einsatz der mesenchymalen Stammzelltherapie einen erfolgversprechenden Therapieansatz für die Zukunft dar.

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