scholarly journals Nuclear Function of Smad7 Promotes Myogenesis

2009 ◽  
Vol 30 (3) ◽  
pp. 722-735 ◽  
Author(s):  
Tetsuaki Miyake ◽  
Nezeka S. Alli ◽  
John C. McDermott
Keyword(s):  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Gene Activation ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Independent Function ◽  
Nuclear Function ◽  
Localization Signal ◽  
Β Receptor

ABSTRACT In the “canonical” view of transforming growth factor β (TGF-β) signaling, Smad7 plays an inhibitory role. While Smad7 represses Smad3 activation by TGF-β, it does not reverse the inhibitory effect of TGF-β on myogenesis, suggesting a different function in myogenic cells. We previously reported a promyogenic role of Smad7 mediated by an interaction with MyoD. Based on this association, we hypothesized a possible nuclear function of Smad7 independent of its role at the level of the receptor. We therefore engineered a chimera of Smad7 with a nuclear localization signal (NLS), which serves to prevent and therefore bypass binding to the TGF-β receptor while concomitantly constitutively localizing Smad7 to the nucleus. This Smad7-NLS did not repress Smad3 activation by TGF-β but did retain its ability to enhance myogenic gene activation and phenotypic myogenesis, indicating that the nuclear, receptor-independent function of Smad7 is sufficient to promote myogenesis. Furthermore, Smad7 physically interacts with MyoD and antagonizes the repressive effects of active MEK on MyoD. Reporter and myogenic conversion assays indicate a pivotal regulation of MyoD transcriptional properties by the balance between Smad7 and active MEK. Thus, Smad7 has a nuclear coactivator function that is independent of TGF-β signaling and necessary to promote myogenic differentiation.

scholarly journals Inhibition of the Transforming Growth Factor β (TGFβ) Pathway by Interleukin-1β Is Mediated through TGFβ-activated Kinase 1 Phosphorylation of SMAD3

2005 ◽  
Vol 16 (8) ◽  
pp. 3501-3510 ◽  
Author(s):  
Germaine F.J.D. Benus ◽  
Albertus T.J. Wierenga ◽  
David J.J. de Gorter ◽  
Jan Jacob Schuringa ◽  
Ariëtte M. van Bennekum ◽  
...  
Keyword(s):  
Growth Factor ◽  
Target Gene ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Acute Phase Proteins ◽  
Gene Activation ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Tgfβ Signaling

Transforming growth factor β is the prototype of a large family of secreted factors that regulate multiple biological processes. In the immune system, TGFβ acts as an anti-inflammatory and immunosuppressive molecule, whereas the cytokine interleukin (IL)-1β is a crucial mediator of inflammatory responses and induces proinflammatory genes and acute phase proteins. Here, we present evidence for the existence of a direct inhibitory interaction between the IL-1β and TGFβ signaling cascades that is not dependent on IL-1β–induced SMAD7 expression. IL-1β and its downstream mediator TAK1 inhibit SMAD3-mediated TGFβ target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGFβ are not affected. IL-1β transiently induces association between TAK1 and the MAD homology 2 domain of SMAD3, resulting in SMAD3 phosphorylation. Furthermore, IL-1β alleviates the inhibitory effect of TGFβ on in vitro hematopoietic myeloid colony formation. In conclusion, our data provide evidence for the existence of a direct inhibitory effect of the IL-1β-TAK1 pathway on SMAD3-mediated TGFβ signaling, resulting in reduced TGFβ target gene activation and restored proliferation of hematopoietic progenitors.

scholarly journals TAZ exhibits phase separation properties and interacts with Smad7 and β-catenin to repress skeletal myogenesis

2021 ◽  
Author(s):  
Soma Tripathi ◽  
Tetsuaki Miyake ◽  
Jonathan Kelebeev ◽  
John C. McDermott
Keyword(s):  
Phase Separation ◽  
Protein Level ◽  
Hip Hop ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Gene Promoter ◽  
Transforming Growth Factor Β ◽  
Hippo Signaling ◽  
Nuclear Speckles

Hippo signaling in Drosophila and mammals is prominent in regulating cell proliferation, death and differentiation. Hippo signaling effectors (YAP/TAZ) exhibit crosstalk with transforming growth factor-β (TGF-β)-Smad and Wnt-β-catenin pathways. Previously, we implicated Smad7 and β-catenin in myogenesis. Therefore, we assessed a potential role of TAZ on theSmad7/β-catenin complex in muscle cells. Here, we document functional interactions between Smad7, TAZ and β-catenin in myogenic cells. Ectopic TAZ expression resulted in repression of the muscle-specific creatine kinase muscle (ckm) gene promoter and its corresponding protein level. Depletion of endogenous TAZ enhanced ckm promoter activation. Ectopic TAZ, while potently active on a TEAD reporter (HIP-HOP), repressed myogenin and myod enhancer regions and Myogenin protein level. Additionally, a Wnt/β-catenin readout (TOP flash) demonstrated TAZ inhibition of β-catenin activity. In myoblasts, TAZ is predominantly localized in nuclear speckles, while in differentiation conditions TAZ is hyperphosphorylated at Ser 89 leading to enhanced cytoplasmic sequestration. Finally, live cell imaging indicates that TAZ exhibits properties of liquid-liquid phase separation (LLPS). These observations indicate that TAZ, as an effector of Hippo signaling, supresses the myogenic differentiation machinery.

Evaluation of incidence, significance, and prognostic role of circulating tumor microemboli and transforming growth factor-β receptor I in head and neck cancer

Head & Neck ◽  
2017 ◽  
Vol 39 (11) ◽  
pp. 2283-2292 ◽  
Author(s):  
Marcello Ferretti Fanelli ◽  
Thiago Bueno Oliveira ◽  
Alexcia Camila Braun ◽  
Marcelo Corassa ◽  
Emne Ali Abdallah ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Growth Factor ◽  
Head And Neck ◽  
Neck Cancer ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Prognostic Role ◽  
Β Receptor ◽  
Circulating Tumor Microemboli

scholarly journals TGF-β signaling is essential for joint morphogenesis

2007 ◽  
Vol 177 (6) ◽  
pp. 1105-1117 ◽  
Author(s):  
Anna Spagnoli ◽  
Lynda O'Rear ◽  
Ronald L. Chandler ◽  
Froilan Granero-Molto ◽  
Douglas P. Mortlock ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Receptor Gene ◽  
Artificial Chromosome ◽  
Transforming Growth Factor Β ◽  
Gene Expressions ◽  
Β Receptor ◽  
Green Fluorescent

Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor β (TGF-β) signaling in mice lacking the TGF-β type II receptor gene (Tgfbr2) in their limbs (Tgfbr2PRX-1KO). In Tgfbr2PRX-1KO mice, the loss of TGF-β responsiveness resulted in the absence of interphalangeal joints. The Tgfbr2Prx1KO joint phenotype is similar to that in patients with symphalangism (SYM1-OMIM185800). By generating a Tgfbr2–green fluorescent protein–β–GEO–bacterial artificial chromosome β-galactosidase reporter transgenic mouse and by in situ hybridization and immunofluorescence, we determined that Tgfbr2 is highly and specifically expressed in developing joints. We demonstrated that in Tgfbr2PRX-1KO mice, the failure of joint interzone development resulted from an aberrant persistence of differentiated chondrocytes and failure of Jagged-1 expression. We found that TGF-β receptor II signaling regulates Noggin, Wnt9a, and growth and differentiation factor-5 joint morphogenic gene expressions. In Tgfbr2PRX-1KO growth plates adjacent to interphalangeal joints, Indian hedgehog expression is increased, whereas Collagen 10 expression decreased. We propose a model for joint development in which TGF-β signaling represents a means of entry to initiate the process.

scholarly journals Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis

2015 ◽  
Vol 75 (3) ◽  
pp. 609-616 ◽  
Author(s):  
Michal Tomcik ◽  
Katrin Palumbo-Zerr ◽  
Pawel Zerr ◽  
Barbora Sumova ◽  
Jerome Avouac ◽  
...  
Keyword(s):  
Cell Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Cultured Fibroblasts ◽  
Fibroblast Activation ◽  
Modulation Of Gene Expression ◽  
Β Receptor ◽  
Interfering Rna

ObjectivesTribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc).MethodsThe expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3.ResultsTRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation.ConclusionsThe present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc.

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