scholarly journals SMAD2 promotes myogenin expression and terminal myogenic differentiation

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev195495
Author(s):  
Émilie Lamarche ◽  
Hamood AlSudais ◽  
Rashida Rajgara ◽  
Dechen Fu ◽  
Saadeddine Omaiche ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Transforming Growth Factor Β ◽  
Acute Injury ◽  
Tgfβ Signaling ◽  
Primary Myoblasts ◽  
Tgfβ Receptor ◽  
Differentiation Marker ◽  
Tgfβ Superfamily

ABSTRACTSMAD2 is a transcription factor, the activity of which is regulated by members of the transforming growth factor β (TGFβ) superfamily. Although activation of SMAD2 and SMAD3 downstream of TGFβ or myostatin signaling is known to inhibit myogenesis, we found that SMAD2 in the absence of TGFβ signaling promotes terminal myogenic differentiation. We found that, during myogenic differentiation, SMAD2 expression is induced. Knockout of SMAD2 expression in primary myoblasts did not affect the efficiency of myogenic differentiation but produced smaller myotubes with reduced expression of the terminal differentiation marker myogenin. Conversely, overexpression of SMAD2 stimulated myogenin expression, and enhanced both differentiation and fusion, and these effects were independent of classical activation by the TGFβ receptor complex. Loss of Smad2 in muscle satellite cells in vivo resulted in decreased muscle fiber caliber and impaired regeneration after acute injury. Taken together, we demonstrate that SMAD2 is an important positive regulator of myogenic differentiation, in part through the regulation of Myog.

scholarly journals SMAD2 Promotes Myogenin Expression and Terminal Myogenic Differentiation

2020 ◽  
Author(s):  
Émilie Lamarche ◽  
Hamood AlSudais ◽  
Rashida Rajgara ◽  
Dechen Fu ◽  
Saadeddine Omaiche ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Acute Injury ◽  
Primary Myoblasts ◽  
Tgfβ Receptor ◽  
Summary Statement ◽  
Differentiation Marker ◽  
Tgfβ Superfamily

ABSTRACTSMAD2 is a transcription factor whose activity is regulated by members of the Transforming Growth Factor beta (TGFβ) superfamily. While activation of SMAD2 and SMAD3 downstream of TGFβ or myostatin signaling is known to inhibit myogenesis, we find that SMAD2 in the absence of TGFβ signaling promotes terminal myogenic differentiation. We find that during myogenic differentiation, SMAD2 expression is induced. Knockout of SMAD2 expression in primary myoblasts did not affect the efficiency of myogenic differentiation but produced smaller myotubes with reduced expression of the terminal differentiation marker myogenin. Conversely, overexpression of SMAD2 stimulated myogenin expression, and enhanced both differentiation and fusion, and these effects were independent of classical activation by the TGFβ receptor complex. Loss of Smad2 in muscle satellite cells in vivo resulted in decreased muscle fiber caliber and impaired regeneration after acute injury. Taken together, we demonstrate that SMAD2 is an important positive regulator of myogenic differentiation, in part through the regulation of Myog.SUMMARY STATEMENTTGFβ and SMAD2 are normally associated with inhibition of myogenesis. Our work identifies a pro-myogenic role for SMAD2 during terminal myogenic differentiation, through regulation of Myog and Klf4 expression.

scholarly journals Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 975
Author(s):  
Kara Corps ◽  
Monica Stanwick ◽  
Juliann Rectenwald ◽  
Andrew Kruggel ◽  
Sarah B. Peters
Keyword(s):  
Transforming Growth Factor ◽  
Skeletal Development ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Skeletal Deformities ◽  
Tooth Abnormalities ◽  
Pathological Analysis ◽  
Diaphragmatic Muscle ◽  
Proliferation And Differentiation ◽  
Tgfβ Receptor

Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

scholarly journals Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

2016 ◽  
Vol 113 (43) ◽  
pp. 12192-12197 ◽  
Author(s):  
Jared M. Fischer ◽  
Peter P. Calabrese ◽  
Ashleigh J. Miller ◽  
Nina M. Muñoz ◽  
William M. Grady ◽  
...  
Keyword(s):  
Single Cell ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Cell Lineage ◽  
Transforming Growth Factor Β ◽  
Lineage Tracing ◽  
Secretory Cells ◽  
Cancer Tissue ◽  
Tgfβ Signaling

Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfβR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfβ signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfβ signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfβ signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.

scholarly journals Secretoglobin 3A2 Suppresses Bleomycin-induced Pulmonary Fibrosis by Transforming Growth Factor β Signaling Down-regulation

2011 ◽  
Vol 286 (22) ◽  
pp. 19682-19692 ◽  
Author(s):  
Reiko Kurotani ◽  
Satoshi Okumura ◽  
Tsutomu Matsubara ◽  
Utako Yokoyama ◽  
John R. Buckley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Adult Mice ◽  
Cell Counts ◽  
Expression Of Genes ◽  
Pulmonary Airways

With increasing worldwide rates of morbidity and mortality of pulmonary fibrosis, the development of effective therapeutics for this disease is of great interest. Secretoglobin (SCGB) 3A2, a novel cytokine-like molecule predominantly expressed in pulmonary airways epithelium, exhibits anti-inflammatory and growth factor activities. In the current study SCGB3A2 was found to inhibit TGFβ-induced differentiation of fibroblasts to myofibroblasts, a hallmark of the fibrogenic process, using pulmonary fibroblasts isolated from adult mice. This induction was through increased phosphorylation of STAT1 and expression of SMAD7 and decreased phosphorylation of SMAD2 and SMAD3. To demonstrate the effect of SCGB3A2 on the TGFβ signaling in vivo, a bleomycin-induced pulmonary fibrosis mouse model was used. Mice were administered bleomycin intratracheally followed by intravenous injection of recombinant SCGB3A2. Histological examination in conjunction with inflammatory cell counts in bronchoalveolar lavage fluids demonstrated that SCGB3A2 suppressed bleomycin-induced pulmonary fibrosis. Microarray analysis was carried out using RNAs from lungs of bleomycin-treated mice with or without SCGB3A2 and normal mice treated with SCGB3A2. The results demonstrated that SCGB3A2 affects TGFβ signaling and reduces the expression of genes involved in fibrosis. This study suggests the potential utility of SCGB3A2 for targeting TGFβ signaling in the treatment of pulmonary fibrosis.

scholarly journals Heart and Liver Defects and Reduced Transforming Growth Factor β2 Sensitivity in Transforming Growth Factor β Type III Receptor-Deficient Embryos

2003 ◽  
Vol 23 (12) ◽  
pp. 4371-4385 ◽  
Author(s):  
Kaye L. Stenvers ◽  
Melinda L. Tursky ◽  
Kenneth W. Harder ◽  
Nicole Kountouri ◽  
Supavadee Amatayakul-Chantler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Gene Activation ◽  
Transforming Growth Factor Β ◽  
Somatic Development ◽  
Type Iii ◽  
Tgfβ Receptor ◽  
Primary Fibroblasts ◽  
Signaling Receptors

ABSTRACT The type III transforming growth factor β (TGFβ) receptor (TβRIII) binds both TGFβ and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of TβRIII signaling in vivo is not known. In this study, we have sought to determine the role of TβRIII during development. We identified the predominant expression sites of ΤβRIII mRNA as liver and heart during midgestation and have disrupted the murine TβRIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in ΤβRIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that TβRIII is required during murine somatic development. To assess the effects of the absence of TβRIII on the function of its ligands, primary fibroblasts were generated from TβRIII-null and wild-type embryos. Our results indicate that TβRIII deficiency differentially affects the activities of TGFβ ligands. Notably, TβRIII-null cells exhibited significantly reduced sensitivity to TGFβ2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that TβRIII is an important modulator of TGFβ2 function in embryonic fibroblasts and that reduced sensitivity to TGFβ2 may underlie aspects of the TβRIII mutant phenotype.

scholarly journals Role of reduced expression of SMAD4 in papillary thyroid carcinoma

2010 ◽  
Vol 45 (4) ◽  
pp. 229-244 ◽  
Author(s):  
Sonia D'Inzeo ◽  
Arianna Nicolussi ◽  
Antonella Ricci ◽  
Patrizia Mancini ◽  
Antonio Porcellini ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Biological Effects ◽  
Transforming Growth Factor Β ◽  
Papillary Thyroid ◽  
Tgfβ Signaling ◽  
Strong Reduction ◽  
Smad4 Protein ◽  
First Time ◽  
Tgfβ Superfamily

It has been demonstrated that transforming growth factor-β (TGFβ) and other members of TGFβ superfamily play an important role in thyroid proliferative diseases. The deficiencies of SMAD4 are responsible to accelerate the malignant progression of neoplastic lesions in several types of tumors. Therefore, the objective of the present study was to determine the functional role of reduced expression of SMAD4 in human papillary thyroid carcinogenesis. For this purpose, we examined the TGFβ response in two cell lines, TPC-1 and BCPAP. Our data demonstrated for the first time that these cells showed a strong reduction in the level of SMAD4 protein, which was responsible for an alteration of TGFβ signaling and for some of the TGFβ-mediated biological effects. The overexpression of SMAD4, restoring TGFβ transduction, determined a significant increase of antiproliferative response to TGFβ, and reduced the invasive behavior of these cells. Therefore, our data indicated that reduction of SMAD4 may play a significant role in thyroid carcinogenesis.

scholarly journals A Role for TGFβ Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression

2021 ◽  
Vol 22 (9) ◽  
pp. 4463
Author(s):  
Julia N. Cheng ◽  
Jennifer B. Frye ◽  
Susan A. Whitman ◽  
Andrew G. Kunihiro ◽  
Ritu Pandey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Bone Metastases ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Tgfβ Receptors ◽  
Mcf 7

While tumoral Smad-mediated transforming growth factor β (TGFβ) signaling drives osteolytic estrogen receptor α-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine Smad-mediated TGFβ signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E2)-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGFβ receptors II and I, only cells with TGFβ-inducible Smad signaling (MCF-7) formed osteolytic BMETs in vivo. Regulated secretion of PTHrP, an osteolytic factor expressed in >90% of clinical BMETs, also tracked with osteolytic potential; TGFβ and E2 each induced PTHrP in bone-tropic or BMET-derived MCF-7 cells, with the combination yielding additive effects, while in cells not forming BMETs, PTHrP was not induced. In vivo treatment with 1D11, a pan-TGFβ neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGFβ may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E2 and TGFβ signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic.

A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys

2020 ◽  
Vol 175 (1) ◽  
pp. 24-34 ◽  
Author(s):  
Mayur S Mitra ◽  
Karla Lancaster ◽  
Adeyemi O Adedeji ◽  
Gopinath S Palanisamy ◽  
Rutwij A Dave ◽  
...  
Keyword(s):  
Small Molecule ◽  
Transforming Growth Factor ◽  
Small Molecule Inhibitors ◽  
Recovery Period ◽  
Transforming Growth Factor Β ◽  
Cardiovascular Toxicity ◽  
Tgfβ Signaling ◽  
Cynomolgus Monkeys ◽  
Tgfβ Receptor ◽  
Neutralizing Monoclonal Antibody

Abstract Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGFβ receptor and not considered to be a liability associated with pan-TGFβ neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFβ neutralizing mAb (pan-TGFβ mAb; neutralizes TGFβ1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at ≥ 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGFβ signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFβ inhibiting mAb.

PGE2 induces angiogenesis via MT1-MMP–mediated activation of the TGFβ/Alk5 signaling pathway

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1120-1128 ◽  
Author(s):  
Arántzazu Alfranca ◽  
Juan Manuel López-Oliva ◽  
Laura Genís ◽  
Dolores López-Maderuelo ◽  
Isabel Mirones ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Kinase Activity ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
In Vivo Models ◽  
Latent Form

Abstract The development of a new vascular network is essential for the onset and progression of many pathophysiologic processes. Cyclooxygenase-2 displays a proangiogenic activity in in vitro and in vivo models, mediated principally through its metabolite prostaglandin E2 (PGE2). Here, we provide evidence for a novel signaling route through which PGE2 activates the Alk5-Smad3 pathway in endothelial cells. PGE2 induces Alk5-dependent Smad3 nuclear translocation and DNA binding, and the activation of this pathway involves the release of active TGFβ from its latent form through a process mediated by the metalloproteinase MT1-MMP, whose membrane clustering is promoted by PGE2. MT1-MMP–dependent transforming growth factor β (TGFβ) signaling through Alk5 is also required for PGE2-induced endothelial cord formation in vitro, and Alk5 kinase activity is required for PGE2-induced neovascularization in vivo. These findings identify a novel signaling pathway linking PGE2 and TGFβ, 2 effectors involved in tumor growth and angiogenesis, and reveal potential targets for the treatment of angiogenesis-related disorders.

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