Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning

Development ◽  
1998 ◽  
Vol 125 (5) ◽  
pp. 857-867 ◽  
Author(s):  
T. Nakayama ◽  
M.A. Snyder ◽  
S.S. Grewal ◽  
K. Tsuneizumi ◽  
T. Tabata ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Neural Induction ◽  
Receptor Activation ◽  
Bmp Signaling ◽  
Serine Phosphorylation ◽  
Specific Gene ◽  
Dorsal Cells

Bone morphogenetic proteins (BMPs) participate in the development of nearly all organs and tissues. BMP signaling is mediated by specific Smad proteins, Smad1 and/or Smad5, which undergo serine phosphorylation in response to BMP-receptor activation and are then translocated to the nucleus where they modulate transcription of target genes. We have identified a distantly related member of the Xenopus Smad family, Smad8, which lacks the C-terminal SSXS phosphorylation motif present in other Smads, and which appears to function in the BMP signaling pathway. During embryonic development, the spatial pattern of expression of Smad8 mirrors that of BMP-4. We show that an intact BMP signaling pathway is required for its expression. Overexpression of Smad8 in Xenopus embryos phenocopies the effect of blocking BMP-4 signaling, leading to induction of a secondary axis on the ventral side of intact embryos and to direct neural induction in ectodermal explants. Furthermore, Smad8 can block BMP-4-mediated induction of ventral mesoderm-specific gene expression in ectodermal explants. Overexpression of Smad8 within dorsal cells, however, causes patterning defects that are distinct from those reported in BMP-4-deficient embryos, suggesting that Smad8 may interact with additional signaling pathways. Indeed, overexpression of Smad8 blocks expression of Xbra in whole animals, and partially blocks activin signaling in animal caps. In addition, Smad8 inhibits involution of mesodermal cells during gastrulation, a phenotype that is not observed following blockade of activin or BMPs in Xenopus. Together, these results are consistent with the hypothesis that Smad8 participates in a negative feedback loop in which BMP signaling induces the expression of Smad8, which then functions to negatively modulate the amplitude or duration of signaling downstream of BMPs and, possibly, downstream of other transforming growth factor-beta (TGF-beta) family ligands.

scholarly journals miR-301a-5p Regulates TGFB2 during Chicken Spermatogenesis

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1695
Author(s):  
Qixin Guo ◽  
Yong Jiang ◽  
Hao Bai ◽  
Guohong Chen ◽  
Guobin Chang
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Cell Types ◽  
Germline Cell ◽  
Micro Rnas ◽  
Growth Factor Beta

The process of spermatogenesis is complex and systemic, requiring the cooperation of many regulators. However, little is known about how micro RNAs (miRNAs) regulate spermatogenesis in poultry. In this study, we investigated key miRNAs and their target genes that are involved in spermatogenesis in chickens. Next-generation sequencing was conducted to determine miRNA expression profiles in five cell types: primordial germ cells (PGCs), spermatogonial stem cells (SSCs), spermatogonia (Spa), and chicken sperm. Next, we analyzed and identified several key miRNAs that regulate spermatogenesis in the four germline cell miRNA profiles. Among the enriched miRNAs, miRNA-301a-5p was the key miRNA in PGCs, SSCs, and Spa. Through reverse transcription quantitative PCR (RT-qPCR), dual-luciferase, and miRNA salience, we confirmed that miR-301a-5p binds to transforming growth factor-beta 2 (TGFβ2) and is involved in the transforming growth factor-beta (TGF-β) signaling pathway and germ cell development. To the best of our knowledge, this is the first demonstration of miR-301a-5p involvement in spermatogenesis by direct binding to TGFβ2, a key gene in the TGF-β signaling pathway. This finding contributes to the insights into the molecular mechanism through which miRNAs regulate germline cell differentiation and spermatogenesis in chickens.

Dynamic Tensile Loading Activates TGF and BMP Signaling in Mesenchymal Stem Cells on Aligned Nanofibrous Scaffolds

2012 ◽  
Author(s):  
Su-Jin Heo ◽  
Tristan P. Driscoll ◽  
Robert L. Mauck
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transforming Growth Factor Beta ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Nanofibrous Scaffolds ◽  
Smad Phosphorylation

Mesenchymal stem cells (MSCs) are a promising cell source for tissue engineering applications, given their ease of isolation and multi-potential differentiation capacity [1]. External mechanical cues directly influence MSC lineage commitment [2]. However, it is not yet clear how these physical cues are transduced to the cell nucleus, an understanding of which may prove essential for orthopaedic tissue engineering. Transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP), members of the TGF beta superfamily, regulate cellular processes including growth and differentiation [3, 4]. TGF and/or BMP ligand binding initiate SMAD phosphorylation, translocation to the nucleus, and transcriptional activation of target genes [4]. Additionally, both ligands can influence the organization of chromatin and the Lamin A/C (LMAC) nucleoskeletal network [5]. For example, we have recently shown that TGF-β3 leads to corticalized LMAC, marked increases in heterochromatin (HTC), and increased nuclear stiffness [6]. Interestingly, dynamic tensile stretch of MSCs on aligned nanofibrous scaffolds, in the absence of these differentiation factors, resulted in many of these same nuclear transformations [6, 7]. The objective of this study was to identify how dynamic tensile stress is transduced in MSCs on aligned nanofibrous scaffolds, and further, to ascertain whether these mechanoregulatory changes are coordinated through TGFβ/BMP signaling pathways.

scholarly journals Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis

2020 ◽  
Author(s):  
Andrew S. Riching ◽  
Etienne Danis ◽  
Yuanbiao Zhao ◽  
Yingqiong Cao ◽  
Congwu Chi ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Epigenetic Mechanism ◽  
Gene Promoters ◽  
Pathway Activation ◽  
Cardiac Gene ◽  
Growth Factor Beta ◽  
Heart Injury ◽  
Cardiac Transcription Factors

SummaryDirect reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF-β) inhibition efficiently promotes reprogramming. However, the mechanisms by which TGF-β blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3) – demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGF-β signaling regulates the interaction between GATA4 and JMJD3. TGF-β activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation in GATA4 (V267M) exhibits reduced binding to JMJD3 and impaired cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGF-β pathway activation impairs cardiac gene programming by interfering with GATA4-JMJD3 interactions.

Endogenous patterns of TGFbeta superfamily signaling during early Xenopus development

Development ◽  
2000 ◽  
Vol 127 (13) ◽  
pp. 2917-2931 ◽  
Author(s):  
S. Faure ◽  
M.A. Lee ◽  
T. Keller ◽  
P. ten Dijke ◽  
M. Whitman
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Xenopus Embryo ◽  
Bmp Signaling ◽  
Type I ◽  
Embryonic Cells ◽  
Xenopus Development ◽  
Zygotic Transcription ◽  
Carboxy Terminal

Transforming growth factor beta (TGFbeta) superfamily signaling has been implicated in patterning of the early Xenopus embryo. Upon ligand stimulation, TGFbeta receptors phosphorylate Smad proteins at carboxy-terminal SS(V/M)S consensus motifs. Smads 1/5/8, activated by bone morphogenetic protein (BMP) signaling, induce ventral mesoderm whereas Smad2, activated by activin-like ligands, induces dorsal mesoderm. Although ectopic expression studies are consistent with roles for TGFbeta signals in early Xenopus embryogenesis, when and where BMP and activin-like signaling pathways are active endogenously has not been directly examined. In this study, we investigate the temporal and spatial activation of TGFbeta superfamily signaling in early Xenopus development by using antibodies specific for the type I receptor-phosphorylated forms of Smad1/5/8 and Smad2. We find that Smad1/5/8 and two distinct isoforms of Smad2, full-length Smad2 and Smad2(delta)exon3, are phosphorylated in early embryos. Both Smad1/5/8 and Smad2/Smad2(delta)exon3 are activated after, but not before, the mid-blastula transition (MBT). Endogenous activation of Smad2/Smad2(delta)exon3 requires zygotic transcription, while Smad1/5/8 activation at MBT appears to involve transcription-independent regulation. We also find that the competence of embryonic cells to respond to TGF(delta) superfamily ligands is temporally regulated and may be a determinant of early patterning. Levels of phospho-Smad1/5/8 and of phospho-Smad2/Smad2(delta)exon3 are asymmetrically distributed across both the animal-vegetal and dorsoventral axes. The timing of the development of these asymmetries differs for phospho-Smad1/5/8 and for phospho-Smad2/Smad2(delta)exon3, and the spatial distribution of phosphorylation of each Smad changes dramatically as gastrulation begins. We discuss the implications of our results for endogenous functions of BMP and activin-like signals as candidate morphogens regulating primary germ layer formation and dorsoventral patterning of the early Xenopus embryo.

scholarly journals Disruption of Smad4 in Odontoblasts Causes Multiple Keratocystic Odontogenic Tumors and Tooth Malformation in Mice

2009 ◽  
Vol 29 (21) ◽  
pp. 5941-5951 ◽  
Author(s):  
Yuanrong Gao ◽  
Guan Yang ◽  
Tujun Weng ◽  
Juan Du ◽  
Xuejiu Wang ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Odontogenic Tumors ◽  
High Recurrence Rate ◽  
Signal Molecules ◽  
Cystic Tumors ◽  
Keratocystic Odontogenic Tumors

ABSTRACT Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocyte-specific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-β/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment.

scholarly journals Contextual Regulation of TGF-β Signaling in Liver Cancer

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1235 ◽  
Author(s):  
Tu ◽  
Huang ◽  
Huang ◽  
Luo ◽  
Yan
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Primary Liver Cancer ◽  
Receptor Activation ◽  
Membrane Receptors ◽  
Cancer Cell Survival

Primary liver cancer is one of the leading causes for cancer-related death worldwide. Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that signals through membrane receptors and intracellular Smad proteins, which enter the nucleus upon receptor activation and act as transcription factors. TGF-β inhibits liver tumorigenesis in the early stage by inducing cytostasis and apoptosis, but promotes malignant progression in more advanced stages by enhancing cancer cell survival, EMT, migration, invasion and finally metastasis. Understanding the molecular mechanisms underpinning the multi-faceted roles of TGF-β in liver cancer has become a persistent pursuit during the last two decades. Contextual regulation fine-tunes the robustness, duration and plasticity of TGF-β signaling, yielding versatile albeit specific responses. This involves multiple feedback and feed-forward regulatory loops and also the interplay between Smad signaling and non-Smad pathways. This review summarizes the known regulatory mechanisms of TGF-β signaling in liver cancer, and how they channel, skew and even switch the actions of TGF-β during cancer progression.

scholarly journals Targeting TGF-β-Mediated SMAD Signaling Pathway via Novel Recombinant Cytotoxin II: A Potent Protein from Naja naja oxiana Venom in Melanoma

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5148
Author(s):  
Afshin Derakhshani ◽  
Nicola Silvestris ◽  
Nima Hemmat ◽  
Zahra Asadzadeh ◽  
Mahdi Abdoli Shadbad ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Melanoma Cells ◽  
Smad Signaling ◽  
Diphenyltetrazolium Bromide ◽  
Smad Signaling Pathway ◽  
Matrix Metallopeptidase ◽  
Tumoral Cells

Since the current treatments have not resulted in the desired outcomes for melanoma patients, there is a need to identify more effective medications. Together with other snake venom proteins, cytotoxin-II has shown promising results in tumoral cells. In this study, recombinant cytotoxin-II (rCTII) was expressed in SHuffle® T7 Express cells, while the epitope mapping of rCTII was performed to reveal the antibody-binding regions of rCTII. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to assess the viability of SK-MEL-3 and HFF-2 cells after treating these cells with rCTII. The qRT-PCR was performed to evaluate the expression levels of matrix metallopeptidase 3 (MMP-3), SMAD2, SMAD3, caspase-8, caspase-9, and miR-214 in order to reveal the rCTII-induced signaling pathways in melanoma. Our results have shown that two regions of amino acids, 6–16 and 19–44, as predicted epitopes of this toxin, are essential for understanding the toxicity of rCTII. Treating the melanoma cells with rCTII substantially inhibited the transforming growth factor-beta (TGF-β)–SMAD signaling pathway and down-regulated the expression of MMP-3 and miR-214 as well. This cytotoxin also restored apoptosis mainly via the intrinsic pathway. The down-regulation of MMP-3 and miR-214 might be associated with the anti-metastatic property of rCTII in melanoma. The inhibitory effect of rCTII on the TGF-β signaling pathway might be associated with increased apoptosis and decreased cancer cell proliferation. It is interesting to see that the IC50 value of rCTII has been lower in the melanoma cells than non-tumoral cells, which may indicate its potential effects as a drug. In conclusion, rCTII, as a novel medication, might serve as a potent and efficient anticancer drug in melanoma.

scholarly journals Transforming Growth Factor-Beta (TGFβ) Signaling Pathway in Cholangiocarcinoma

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 960 ◽  
Author(s):  
Panagiotis Papoutsoglou ◽  
Corentin Louis ◽  
Cédric Coulouarn
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Efficient Treatment ◽  
Tumor Onset ◽  
Tgfβ Signaling Pathway

Cholangiocarcinoma is a deadly cancer worldwide, associated with a poor prognosis and limited therapeutic options. Although cholangiocarcinoma accounts for less than 15% of liver primary cancer, its silent nature restricts early diagnosis and prevents efficient treatment. Therefore, it is of clinical relevance to better understand the molecular basis of cholangiocarcinoma, including the signaling pathways that contribute to tumor onset and progression. In this review, we discuss the genetic, molecular, and environmental factors that promote cholangiocarcinoma, emphasizing the role of the transforming growth factor β (TGFβ) signaling pathway in the progression of this cancer. We provide an overview of the physiological functions of TGFβ signaling in preserving liver homeostasis and describe how advanced cholangiocarcinoma benefits from the tumor-promoting effects of TGFβ. Moreover, we report the importance of noncoding RNAs as effector molecules downstream of TGFβ during cholangiocarcinoma progression, and conclude by highlighting the need for identifying novel and clinically relevant biomarkers for a better management of patients with cholangiocarcinoma.

scholarly journals MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

2015 ◽  
Vol 35 (1) ◽  
pp. 213-226 ◽  
Author(s):  
Xin Zhao ◽  
Kejing Wang ◽  
Yuhua Liao ◽  
Qiutang Zeng ◽  
Yushu Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Luciferase Reporter ◽  
Migration Ability

Background/Aims: Hypoxia is a basic pathological challenge that is associated with numerous cardiovascular disorders including aberrant cardiac remodeling. Transforming growth factor beta (TGF-β) signaling pathway plays a pivotal role in mediating cardiac fibroblast (CF) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac remodeling and improved cardiac function. This study aimed to investigate the potential relationship between hypoxia, miR-101a and TGF-β signaling pathway in CFs. Methods and Results: Two weeks following coronary artery occlusion in rats, the expression levels of both TGFβ1 and TGFβRI were increased, but the expression of miR-101a was decreased at the site of the infarct and along its border. Cultured rat neonatal CFs treated with hypoxia were characterized by the up-regulation of TGFβ1 and TGFβRI and the down-regulation of miR-101a. Delivery of miR-101a mimics significantly suppressed the expression of TGFβRI and p-Smad 3, CF differentiation and collagen content of CFs. These anti-fibrotic effects were abrogated by co-transfection with AMO-miR-101a, an antisense inhibitor of miR-101a. The repression of TGFβRI, a target of miR-101a, was validated by luciferase reporter assays targeting the 3'UTR of TGFβRI. Additionally, we found that overexpression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia. Conclusion: Our study illustrates that miR-101a exerts anti-fibrotic effects by targeting TGFβRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-β signaling pathway and cardiac fibrosis.

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