scholarly journals Functions of Transforming Growth Factor-β Family Type I Receptors and Smad Proteins in the Hypertrophic Maturation and Osteoblastic Differentiation of Chondrocytes

2002 ◽  
Vol 277 (37) ◽  
pp. 33545-33558 ◽  
Author(s):  
Ulrich Valcourt ◽  
Jérôme Gouttenoire ◽  
Aristidis Moustakas ◽  
Daniel Herbage ◽  
Frédéric Mallein-Gerin
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Osteoblastic Differentiation ◽  
Family Type ◽  
Type I ◽  
Smad Proteins

scholarly journals STRAP and Smad7 Synergize in the Inhibition of Transforming Growth Factor β Signaling

2000 ◽  
Vol 20 (9) ◽  
pp. 3157-3167 ◽  
Author(s):  
Pran K. Datta ◽  
Harold L. Moses
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Transcriptional Responses ◽  
C Terminus ◽  
Smad Proteins

ABSTRACT Smad proteins play a key role in the intracellular signaling of the transforming growth factor β (TGF-β) superfamily of extracellular polypeptides that initiate signaling from the cell surface through serine/threonine kinase receptors. A subclass of Smad proteins, including Smad6 and Smad7, has been shown to function as intracellular antagonists of TGF-β family signaling. We have previously reported the identification of a WD40 repeat protein, STRAP, that associates with both type I and type II TGF-β receptors and that is involved in TGF-β signaling. Here we demonstrate that STRAP synergizes specifically with Smad7, but not with Smad6, in the inhibition of TGF-β-induced transcriptional responses. STRAP does not show cooperation with a C-terminal deletion mutant of Smad7 that does not bind with the receptor and consequently has no inhibitory activity. STRAP associates stably with Smad7, but not with the Smad7 mutant. STRAP recruits Smad7 to the activated type I receptor and forms a complex. Moreover, STRAP stabilizes the association between Smad7 and the activated receptor, thus assisting Smad7 in preventing Smad2 and Smad3 access to the receptor. STRAP interacts with Smad2 and Smad3 but does not cooperate functionally with these Smads to transactivate TGF-β-dependent transcription. The C terminus of STRAP is required for its phosphorylation in vivo, which is dependent on the TGF-β receptor kinases. Thus, we describe a mechanism to explain how STRAP and Smad7 function synergistically to block TGF-β-induced transcriptional activation.

scholarly journals Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on β1-Integrin To Promote Normal Liver Development

2001 ◽  
Vol 21 (15) ◽  
pp. 5122-5131 ◽  
Author(s):  
Michael Weinstein ◽  
Satdarshan P. S. Monga ◽  
Ye Liu ◽  
Steven G. Brodie ◽  
Yi Tang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Type I ◽  
Β1 Integrin ◽  
Adhesive Properties ◽  
Regulatory Pathways ◽  
Smad Proteins ◽  
Hepatocyte Growth

ABSTRACT Smads serve as intracellular mediators of transforming growth factor β (TGF-β) signaling. After phosphorylation by activated type I TGF-β receptors, Smad proteins translocate to the nucleus, where they serve as transcription factors and increase or decrease expression of TGF-β target genes. Mice lacking one copy each ofSmad2 and Smad3 suffered midgestation lethality due to liver hypoplasia and anemia, suggesting essential dosage requirements of TGF-β signal components. This is likely due to abnormal adhesive properties of the mutant hepatocytes, which may result from a decrease in the level of the β1-integrin and abnormal processing and localization of E-cadherin. Culture of mutant livers in vitro revealed the existence of a parallel developmental pathway mediated by hepatocyte growth factor (HGF), which could rescue the mutant phenotype independent of Smad activation. These pathways merge at the β1-integrin, the level of which was increased by HGF in the cultured mutant livers. HGF treatment reversed the defects in cell proliferation and hepatic architecture in theSmad2 +/− ; Smad3 +/− livers.

scholarly journals Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

2007 ◽  
Vol 282 (14) ◽  
pp. 10405-10413 ◽  
Author(s):  
Jaspreet Pannu ◽  
Sashidhar Nakerakanti ◽  
Edwin Smith ◽  
Peter ten Dijke ◽  
Maria Trojanowska
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor

scholarly journals Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

2004 ◽  
Vol 24 (6) ◽  
pp. 2546-2559 ◽  
Author(s):  
Joshua P. Frederick ◽  
Nicole T. Liberati ◽  
David S. Waddell ◽  
Yigong Shi ◽  
Xiao-Fan Wang
Keyword(s):  
Growth Factor ◽  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Specific Cell ◽  
Smad Proteins ◽  
Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

The human NUPR1/P8 gene is transcriptionally activated by transforming growth factor β via the SMAD signalling pathway

2012 ◽  
Vol 445 (2) ◽  
pp. 285-293 ◽  
Author(s):  
Roxane M. Pommier ◽  
Johann Gout ◽  
David F. Vincent ◽  
Carla E. Cano ◽  
Bastien Kaniewski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Stress Resistance ◽  
Nuclear Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Transcriptional Level ◽  
Smad Proteins ◽  
Activation Cascade ◽  
Tgfβ Superfamily

NUPR1 (nuclear protein 1), also called P8 (molecular mass 8 kDa) or COM1 (candidate of metastasis 1), is involved in the stress response and in cancer progression. In the present study, we investigated whether human NUPR1 expression was regulated by TGFβ (transforming growth factor β), a secreted polypeptide largely involved in tumorigenesis. We demonstrate that the expression of NUPR1 was activated by TGFβ at the transcriptional level. We show that this activation is mediated by the SMAD proteins, which are transcription factors specifically involved in the signalling of TGFβ superfamily members. NUPR1 promoter analysis reveals the presence of a functional TGFβ-response element binding the SMAD proteins located in the genomic DNA region corresponding to the 5′-UTR (5′-untranslated region). Altogether, the molecular results of the present study, which demonstrate the existence of a TGFβ/SMAD/NUPR1 activation cascade, open the way to consider and investigate further a new mechanism enabling TGFβ to promote tumorigenesis by inducing stress resistance.

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