Positive and negative regulation of TGF-beta signaling

2000 ◽  
Vol 113 (7) ◽  
pp. 1101-1109 ◽  
Author(s):  
K. Miyazono
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Inhibitor ◽  
Cell Types ◽  
Negative Regulation ◽  
Bmp Signaling ◽  
Tgf Beta ◽  
Transcription Complexes ◽  
Nuclear Levels

Cytokines of the transforming growth factor beta (TGF-beta) superfamily, including TGF-betas, activins and bone morphogenetic proteins (BMPs), bind to specific serine/threonine kinase receptors and transmit intracellular signals through Smad proteins. Upon ligand stimulation, Smads move into the nucleus and function as components of transcription complexes. TGF-beta and BMP signaling is regulated positively and negatively through various mechanisms. Positive regulation amplifies signals to a level sufficient for biological activity. Negative regulation occurs at the extracellular, membrane, cytoplasmic and nuclear levels. TGF-beta and BMP signaling is often regulated through negative feedback mechanisms, which limit the magnitude of signals and terminate signaling. Negative regulation is also important for formation of gradients of morphogens, which is crucial in developmental processes. In addition, other signaling pathways regulate TGF-beta and BMP signaling through cross-talk. Nearly 20 BMP isoforms have been identified, and their activities are regulated by various extracellular antagonists. Regulation of TGF-beta signaling might be tightly linked to tumor progression, since TGF-beta is a potent growth inhibitor in most cell types.

scholarly journals Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.

1986 ◽  
Vol 163 (5) ◽  
pp. 1037-1050 ◽  
Author(s):  
J H Kehrl ◽  
L M Wakefield ◽  
A B Roberts ◽  
S Jakowlew ◽  
M Alvarez-Mon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transforming Growth Factor Beta ◽  
Potential Role ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Tgf Beta ◽  
Activated T Cells ◽  
Growth Factor Beta

This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.

scholarly journals Expression of mRNA for IL1 beta, IL6 and TGF beta 1 in developing human bone and cartilage.

1994 ◽  
Vol 42 (6) ◽  
pp. 733-744 ◽  
Author(s):  
R A Dodds ◽  
K Merry ◽  
A Littlewood ◽  
M Gowen
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Close Association ◽  
Interleukin 1 ◽  
Cell Types ◽  
Tgf Beta ◽  
Specific Stage ◽  
Growth Factor Beta

Using in situ hybridization, we investigated the expression of mRNA for interleukin-1 beta (IL1 beta), interleukin-6 (IL6), and transforming growth factor-beta-1 (TGF beta 1) in sections of developing bone in human osteophytes. The expression was related to the cellular activity of alkaline phosphatase to aid in the identification of pre-osteoblast populations. IL1 beta mRNA was localized in active osteoblasts within distinct areas of intramembranous ossification. However, the expression was sporadic and appeared to occur at a specific stage of the osteoblast life cycle. There was no IL1 beta mRNA expression in any cell types during endochondral ossification. IL6 mRNA expression was located within pre-osteoblasts and in newly differentiated and matrix-secreting osteoblasts; expression was absent or reduced in flattened, inactive osteoblasts. Weak or no IL6 expression was observed in chondroblasts and chondrocytes, respectively. However, there was a close association between IL6 mRNA expression and the differentiation of mesenchymal cells into osteoblasts. TGF beta 1 expression was localized to osteoblasts apposed to bone or cartilage matrix; the intensity of expression correlated with matrix secretion. Chondroblasts and chondrocytes expressed lower but significant levels of TGF beta 1 mRNA; the expression was lost with the progression to calcifying cartilage. The three cytokines studied were differentially expressed both temporally and spatially, suggesting different roles for each in osteoblast and chondrocyte function.

scholarly journals Distribution and modulation of the cellular receptor for transforming growth factor-beta.

1987 ◽  
Vol 105 (2) ◽  
pp. 965-975 ◽  
Author(s):  
L M Wakefield ◽  
D M Smith ◽  
T Masui ◽  
C C Harris ◽  
M B Sporn
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Tgf Beta ◽  
Cell Type ◽  
Down Regulation ◽  
Growth Factor Beta ◽  
Different Cell Types

Scatchard analyses of the binding of transforming growth factor-beta (TGF-beta) to a wide variety of different cell types in culture revealed the universal presence of high affinity (Kd = 1-60 pM) receptors for TGF-beta on every cell type assayed, indicating a wide potential target range for TGF-beta action. There was a strong (r = +0.85) inverse relationship between the receptor affinity and the number of receptors expressed per cell, such that at low TGF-beta concentrations, essentially all cells bound a similar number of TGF-beta molecules per cell. The binding of TGF-beta to various cell types was not altered by many agents that affect the cellular response to TGF-beta, suggesting that modulation of TGF-beta binding to its receptor may not be a primary control mechanism in TGF-beta action. Similarly, in vitro transformation resulted in only relatively small changes in the cellular binding of TGF-beta, and for those cell types that exhibited ligand-induced down-regulation of the receptor, down-regulation was not extensive. Thus the strong conservation of binding observed between cell types is also seen within a given cell type under a variety of conditions, and receptor expression appears to be essentially constitutive. Finally, the biologically inactive form of TGF-beta, which constitutes greater than 98% of autocrine TGF-beta secreted by all of the twelve different cell types assayed, was shown to be unable to bind to the receptor without prior activation in vitro. It is proposed that this may prevent premature interaction of autocrine ligand and receptor in the Golgi apparatus.

scholarly journals Cell type-specific control of human neuronectin secretion by polypeptide mediators and phorbol ester.

1989 ◽  
Vol 37 (12) ◽  
pp. 1777-1786 ◽  
Author(s):  
W J Rettig ◽  
P Garin-Chesa
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Malignant Tumors ◽  
Tissue Injury ◽  
Mesenchymal Cell ◽  
Cell Types ◽  
Skin Lesions ◽  
Psoriatic Skin ◽  
Tgf Beta

Neuronectin (NEC1) is a human extracellular matrix (ECM) protein expressed with a unique rostrocaudal pattern in white matter of the normal adult central nervous system. In addition, NEC1 is expressed in normal fetal and adult smooth muscle, along certain epithelial-mesenchymal junctions, and transiently in developing fetal cartilage. Region-specific induction of NEC1 is found in dermal wounds and in the reactive stroma of actinic keratoses, psoriatic skin lesions, and a range of malignant tumors. One explanation for these diverse tissue patterns is that cells capable of producing NEC1 are widely distributed in neural and mesenchymal tissues, but they become NEC1 producers only when induced by region-specific differentiation signals. In this study, we used cultured human cells to show that several regulatory polypeptides, including fibroblast growth factors, tumor necrosis factor, platelet-derived growth factor, nerve growth factor, and transforming growth factor-beta (TGF-beta), as well as 12-O-tetradecanoyl phorbol-13-acetate (TPA), modulate NEC1 secretion, with distinct patterns of inducing and inhibitory activities in different neural and mesenchymal cell types. TPA and TGF-beta act both as inducers and inhibitors of NEC1 secretion, depending on the target cell. These effects are specific for NEC1 and are not seen for several other secreted and membrane proteins studied. We suggest that NEC1 expression comes under different modes of extrinsic control in different cell lineages and in response to tissue injury and neoplasia.

scholarly journals The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1540-1548 ◽  
Author(s):  
T Terui ◽  
Y Niitsu ◽  
K Mahara ◽  
Y Fujisaki ◽  
Y Urushizaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transforming Growth Factor Beta ◽  
Collagen Synthesis ◽  
Transforming Growth Factor ◽  
Leukemic Cell ◽  
Cell Types ◽  
Tgf Beta ◽  
Megakaryoblastic Leukemia ◽  
Bone Marrow Fibroblasts ◽  
Growth Factor Beta

Abstract Acute myelofibrosis is often associated with acute megakaryoblastic leukemia (AMKBL). Although the exact mechanism for the progression of myelofibrosis in AMKBL is unclear, certain humoral factors from megakaryoblastic cells, the precursors of platelets, may be involved in the enhancement of collagen synthesis by bone marrow fibroblasts. The present study, therefore, is an investigation of the possible pathogenic role of transforming growth factor-beta (TGF-beta), known to be a very potent collagen-stimulating factor found in platelets in the myelofibrosis of AMKBL. The results obtained were as follows: (1) Conditioned media from peripheral megakaryoblasts taken from an AMKBL patient and from established megakaryoblast cell lines (MEG-01) had much greater stimulatory effects on collagen synthesis in bone marrow fibroblasts than conditioned media from other leukemic cell types. (2) Based on an assessment of soft agar colony formation, there was greater TGF-beta activity in media that had been conditioned from megakaryoblasts than in media from other leukemic cell types. (3) When compared with other leukemic-cell types, megakaryoblasts showed substantially greater expression of TGF-beta mRNA that was hybridized at 2.5 kb with a TGF-beta cDNA probe, and TGF-beta polypeptides were detected at 13 Kd with anti-TGF-beta antibodies. (4) The addition of the anti-TGF-beta antibody inhibited the stimulatory effects of the megakaryoblast conditioned medium on collagen synthesis in bone marrow fibroblasts. These results clearly suggest that megakaryoblasts produce and secrete an active form of TGF-beta and stimulate collagen synthesis in bone marrow fibroblasts in a paracrine manner.

scholarly journals Non-uniform influence of transforming growth factor-β on the biosynthesis of different forms of small chondroitin sulphate/dermatan sulphate proteoglycan

1990 ◽  
Vol 269 (2) ◽  
pp. 551-554 ◽  
Author(s):  
B Breuer ◽  
G Schmidt ◽  
H Kresse
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Core Protein ◽  
Chondroitin Sulphate ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Osteosarcoma Cell ◽  
Tgf Beta ◽  
Small Proteoglycan

The influence of transforming growth factor-beta (TGF-beta) on the expression of different forms of small proteoglycans was investigated in human skin fibroblasts and in a human osteosarcoma cell line. TGF-beta was not found to act as a general stimulator of small proteoglycan biosynthesis. In both cell types, an increased expression of the core protein of proteoglycan I was found. However, there was a profound decrease in the expression of a 106 kDa core protein, and either no alteration or a small decrease in the biosynthesis of the collagen-binding small proteoglycan II core protein. These results show that the production of individual members of the small proteoglycan family is differentially regulated.

The Drosophila gene Medea demonstrates the requirement for different classes of Smads in dpp signaling

Development ◽  
1998 ◽  
Vol 125 (8) ◽  
pp. 1519-1528 ◽  
Author(s):  
P. Das ◽  
L.L. Maduzia ◽  
H. Wang ◽  
A.L. Finelli ◽  
S.H. Cho ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Bmp Signaling ◽  
Class I ◽  
Tgf Beta ◽  
C Elegans ◽  
Sequence Similarities ◽  
Close Homolog

Signals from transforming growth factor-beta (TGF-beta) ligands are transmitted within the cell by members of the Smad family, which can be grouped into three classes based on sequence similarities. Our previous identification of both class I and II Smads functioning in a single pathway in C. elegans, raised the issue of whether the requirement for Smads derived from different classes is a general feature of TGF-beta signaling. We report here the identification of a new Drosophila class II Smad, Medea, a close homolog of the human tumor-suppressor gene DPC4. Embryos from germline clones of both Medea and Mad (a class I Smad) are ventralized, as are embryos null for the TGF-beta-like ligand decapentaplegic (dpp). Loss of Medea also blocks dpp signaling during later development, suggesting that Medea, like Mad, is universally required for dpp signaling. Furthermore, we show that the necessity for these two closely related, non-redundant Smads, is due to their different signaling properties - upon activation of the Dpp pathway, Mad is required to actively translocate Medea into the nucleus. These results provide a paradigm for, and distinguish between, the requirement for class I and II Smads in Dpp/BMP signaling.

scholarly journals Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta.

1989 ◽  
Vol 109 (6) ◽  
pp. 3137-3145 ◽  
Author(s):  
J L Andres ◽  
K Stanley ◽  
S Cheifetz ◽  
J Massagué
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Core Protein ◽  
Culture Media ◽  
Cell Types ◽  
Type I ◽  
Tgf Beta ◽  
Beta Receptor ◽  
Core Proteins ◽  
Membrane Bound

Transforming growth factors beta 1 and beta 2 bind with high affinity to the core protein of a 250-350-kD cell surface proteoglycan. This proteoglycan (formerly referred to as the type III TGF-beta receptor) coexists in many cells with the receptor implicated in TGF-beta signal transduction (type I TGF-beta receptor), but its function is not known. We report here that soluble TGF-beta-binding proteoglycans are released by several cell types into the culture media, and can be found in serum and extracellular matrices. As has been shown for the membrane-bound form, the soluble proteoglycans have a heterogeneous core protein of 100-120 kD that carries chondroitin sulfate and/or heparan sulfate glycosaminoglycan chains and a small amount of N-linked carbohydrate. The membrane-bound form of this proteoglycan is hydrophobic and associates with liposomes, whereas the soluble forms lack a membrane anchor and do not associate with liposomes. Differences in the electrophoretic migration of the soluble and membrane forms of this proteoglycan suggest additional structural differences in their core proteins and glycosaminoglycan chains. These soluble and membrane-bound proteoglycans, for which we propose the name "betaglycans," might play distinct roles in pericellular retention, delivery, or clearance of activated TGF-beta.

scholarly journals Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2604
Author(s):  
Daisy Y. Shu ◽  
Frank J. Lovicu
Keyword(s):  
Cell Fate ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Bmp Signaling ◽  
The Body ◽  
Ocular Lens ◽  
Mesenchymal Transition

Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell proliferation, differentiation and morphogenesis, throughout the body. In the ocular lens, BMPs are important in orchestrating fundamental developmental processes such as induction of lens morphogenesis, and specialized differentiation of its fiber cells. Moreover, BMPs have been reported to facilitate regeneration of the lens, as well as abrogate pathological processes such as TGFβ-induced epithelial-mesenchymal transition (EMT) and apoptosis. In this review, we summarize recent insights in this topic and discuss the complexities of BMP-signaling including the role of individual BMP ligands, receptors, extracellular antagonists and cross-talk between canonical and non-canonical BMP-signaling cascades in the lens. By understanding the molecular mechanisms underlying BMP activity, we can advance their potential therapeutic role in cataract prevention and lens regeneration.

scholarly journals Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells.

1994 ◽  
Vol 179 (3) ◽  
pp. 999-1004 ◽  
Author(s):  
M Lotz ◽  
E Ranheim ◽  
T J Kipps
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Transforming Growth Factor Beta ◽  
Growth Regulation ◽  
Transforming Growth Factor ◽  
Growth Inhibitor ◽  
Lymphocytic Leukemia ◽  
Tgf Beta

Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refractory to mitogens and growth factors in vitro. This study examined whether transforming growth factor beta (TGF-beta), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-beta 1 mRNA. In vitro release of TGF-beta by unstimulated cultures, or cultures stimulated by antibody to cell surface immunoglobulin (anti-mu) plus phorbol 12-myristate 13-acetate (PMA) was higher in CLL than in normal B cells. High levels of TGF-beta activity were also detected in plasma samples of CLL patients. The role of TGF-beta in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients proliferated in response to anti-mu, or the combination of anti-mu plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when presented on Fc gamma RII (CDw32)-expressing L cells. Neutralizing antibodies to TGF-beta increased CLL B cell proliferation in the absence or presence of additional stimuli. These effects were dose dependent and specific. Exogenous TGF-beta completely inhibited CLL B cell proliferation induced by anti-mu, PMA, and anti-TGF-beta. CLL B cell proliferation induced by anti-CD40 was reduced by exogenous TGF-beta. However, even at high doses, TGF-beta did not completely inhibit the anti-CD40 effect. In summary, TGF-beta is overexpressed in CLL. CLL B cells are sensitive to TGF-beta and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative responses of these leukemic cells and for the slow progression of the malignant process in vivo.

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