scholarly journals Gene expression profiling demonstrates that TGF-β1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-β signaling

2005 ◽  
Vol 21 (3) ◽  
pp. 396-403 ◽  
Author(s):  
Göran Karlsson ◽  
Yingchun Liu ◽  
Jonas Larsson ◽  
Marie-José Goumans ◽  
Ju-Seog Lee ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions ◽  
Murine Embryonic Fibroblast ◽  
Downstream Signaling ◽  
Receptor Complexes ◽  
Downstream Effector ◽  
Β Receptor ◽  
Embryonic Fibroblast ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-β binds to receptor complexes consisting of TGF-β receptor type II (TβRII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of TβRII/Alk5 can be relevant for TGF-β signaling. We have screened for alternative receptors for TGF-β and also for gene targets of TGF-β signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-β-stimulated Alk5−/− cells show them to be completely unaffected by TGF-β. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5−/− or TGF-β-stimulated Alk5+/+ MEFs with unstimulated Alk5+/+ cells. Our results demonstrate that, in MEFs, TGF-β signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.

scholarly journals Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

2014 ◽  
Vol 82 (9) ◽  
pp. 3678-3686 ◽  
Author(s):  
César Echeverría ◽  
Ignacio Montorfano ◽  
Pablo Tapia ◽  
Claudia Riedel ◽  
Claudio Cabello-Verrugio ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Vascular Dysfunction ◽  
Transforming Growth Factor Β1 ◽  
Protein Expression Pattern ◽  
Bacterial Endotoxins ◽  
Β Receptor ◽  
Activated Fibroblasts ◽  
Induced Changes ◽  
Tgf Β1

ABSTRACTDuring endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor β1 (TGF-β1) and TGF-β2. However, whether TGF-β1 and TGF-β2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-β receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-β production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-β1 and TGF-β2. Endotoxin-treated ECs induced the expression and secretion of TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins α-SMA and fibronectin. Thus, endotoxin induces the production of TGF-β1 and TGF-β2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-β secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.

Receptor mimicking TGF-β1 binding peptide for targeting TGF-β1 signaling

2021 ◽  
Author(s):  
David G. Belair ◽  
Jae Sung Lee ◽  
Anna V. Kellner ◽  
Johnny Huard ◽  
William L. Murphy
Keyword(s):  
Biological Activity ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Soluble Form ◽  
Receptor Complex ◽  
Binding Peptide ◽  
Binding Peptides ◽  
Β Receptor ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) binding peptides were developed via biomimicry of the TGF-β1/TGF-β receptor complex to attenuate biological activity of TGF-β1 when presented either in soluble form or conjugated to synthetic biomaterials.

scholarly journals Transforming growth factor β1 attenuates ceramide-induced CPP32/Yama activation and apoptosis in human leukaemic HL-60 cells

1997 ◽  
Vol 327 (3) ◽  
pp. 663-667 ◽  
Author(s):  
Min-Liang KUO ◽  
Chien-Wei CHEN ◽  
Shiou-Hwa JEE ◽  
Shuang-En CHUANG ◽  
Ann-Lii CHENG
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Second Messenger ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Tgf Β1

Ceramide, a product of sphingomyelin turnover, is a novel lipid second messenger that mediates important cellular functions including proliferation, differentiation and apoptosis. This study demonstrates that the CPP32/Yama protease was activated during apoptosis induced by the membrane-permeable second messenger C2-ceramide in HL-60 cells. We also found that the addition of a specific tetrapeptide inhibitor of CPP32/Yama, Ac-DEVD-CHO, provided an effective protection against ceramide-induced cell death. These results suggested that CPP32/Yama has a central role in ceramide-mediated apoptosis. Furthermore a wide variety of cytokines were examined for their effect on ceramide-induced apoptosis. Only transforming growth factor β1 (TGF-β1) (1 ng/ml) exerted significant prevention of apoptosis induced by C2-ceramide, or by sphingomyelinase (increases intracellular ceramide). Consistently, TGF-β1 abrogated the cleavage of poly(ADP-ribose) polymerase and the production of the CPP32/Yama active subunit, p17. However, TGF-β1 treatment did not cause growth inhibition or alter the level of cyclin-dependent kinase inhibitor p27. It suggests that the preventive effect of TGF-β1 is not mediated by growth arrest. Interestingly, we found that TGF-β1 prevented the C2-ceramide-caused decrease of Bcl-2 protein. We thus propose that TGF-β1 rescues ceramide-induced cell death, possibly by maintaining the constant level of Bcl-2, thereby abolishing CPP32/Yama protease activation.

Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1961-1970 ◽  
Author(s):  
Sumio Sakamaki ◽  
Yasuo Hirayama ◽  
Takuya Matsunaga ◽  
Hiroyuki Kuroda ◽  
Toshiro Kusakabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Transforming Growth Factor Β1 ◽  
Lineage Specificity ◽  
Β Receptor ◽  
Tgf Β1

Abstract The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

scholarly journals Cloning of Transforming Growth Factor-β1 (TGF-β1) and Its Type II Receptor from Zebrafish Ovary and Role of TGF-β1 in Oocyte Maturation

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 1931-1941 ◽  
Author(s):  
Gurneet Kohli ◽  
Siqin Hu ◽  
Eric Clelland ◽  
Tamara Di Muccio ◽  
Jeffrey Rothenstein ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Kinase Domain ◽  
Dependent Manner ◽  
Type Ii ◽  
Downstream Signaling ◽  
High Level ◽  
Tgf Β1

TGF-β is a multifunctional factor involved in regulating a variety of cellular activities. In mammals, TGF-β is known to regulate reproduction, including ovarian functions. The role of TGF-β in lower vertebrates, such as fish, is poorly understood. To examine the role of TGF-β in fish reproduction, cDNAs encoding TGF-β1 and the type II TGF-β receptor (TβRII) were cloned from the zebrafish ovary using PCR- based strategies. The mature peptide region of the zebrafish TGF-β1 shows 70–85% identity with TGF-β1 from other species. The zebrafish TβRII cDNA sequence is the first to be reported from a fish species, and it shows a high level of conservation at the kinase domain. Using RT-PCR, we have detected mRNA expression of TGF-β1, TβRII, as well as its downstream signaling molecules Smad2, 3, and 4 in ovarian follicles at different stages of development. In addition, we have examined the effect of TGF-β1 on oocyte maturation. TGF-β1 significantly inhibited both gonadotropin- and 17α, 20β-dihydroxyprogesterone-induced oocyte maturation in a dose- and time-dependent manner. These findings demonstrate, for the first time, that TGF-β1 plays a role in regulating oocyte maturation in fish and suggest that a TGF-β/Smad signaling pathway is present in the zebrafish ovary.

scholarly journals Laminin γ2–mediating T cell exclusion attenuates response to anti–PD-1 therapy

2021 ◽  
Vol 7 (6) ◽  
pp. eabc8346 ◽  
Author(s):  
Lei Li ◽  
Jia-Ru Wei ◽  
Jun Dong ◽  
Qing-Guang Lin ◽  
Hong Tang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Mouse Tumor ◽  
Chemotherapy Drugs ◽  
T Cell Infiltration ◽  
Clinical Benefits ◽  
Β Receptor ◽  
Tgf Β1

PD-1/PD-L1 blockade therapies provide notable clinical benefits for patients with advanced cancers, but the factors influencing the effectiveness of the treatment remain incompletely cataloged. Here, the up-regulation of laminin γ2 (Ln-γ2) predicted the attenuated efficacy of anti–PD-1 drugs and was associated with unfavorable outcomes in patients with lung cancer or esophageal cancer. Furthermore, Ln-γ2 was transcriptionally activated by transforming growth factor–β1 (TGF-β1) secreted from cancer-associated fibroblasts via JNK/AP1 signaling, which blocked T cell infiltration into the tumor nests by altering the expression of T cell receptors. Coadministration of the TGF-β receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti–PD-1 therapy in mouse tumor models. Therefore, Ln-γ2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti–PD-1 drugs.

Modulation of Sensitivity to Transforming Growth Factor-β1 (TGF-β1) and the Level of Type II TGF-β Receptor in LNCaP Cells by Dihydrotestosterone

1996 ◽  
Vol 222 (1) ◽  
pp. 103-110 ◽  
Author(s):  
Isaac Yi Kim ◽  
David J. Zelner ◽  
Julia A. Sensibar ◽  
Han-Jong Ahn ◽  
Linda Park ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Type Ii ◽  
Lncap Cells ◽  
Β Receptor ◽  
Tgf Β1

Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1961-1970 ◽  
Author(s):  
Sumio Sakamaki ◽  
Yasuo Hirayama ◽  
Takuya Matsunaga ◽  
Hiroyuki Kuroda ◽  
Toshiro Kusakabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
High Specificity ◽  
Transforming Growth Factor Β1 ◽  
Lineage Specificity ◽  
Β Receptor ◽  
Tgf Β1

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-β1 (TGF-β1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-β receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-β1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit–granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-β1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-β1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

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