scholarly journals Up-regulated Transcriptional Repressors SnoN and Ski Bind Smad Proteins to Antagonize Transforming Growth Factor-β Signals during Liver Regeneration

2002 ◽  
Vol 277 (32) ◽  
pp. 28483-28490 ◽  
Author(s):  
Marina Macı́as-Silva ◽  
Wei Li ◽  
Julia I. Leu ◽  
Mary Ann S. Crissey ◽  
Rebecca Taub
Keyword(s):  
Growth Factor ◽  
Liver Regeneration ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Transcriptional Repressors ◽  
Smad Proteins

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.

scholarly journals CREB binding protein is a required coactivator for Smad-dependent, transforming growth factor β transcriptional responses in endothelial cells

1998 ◽  
Vol 95 (16) ◽  
pp. 9506-9511 ◽  
Author(s):  
James N. Topper ◽  
Maria R. DiChiara ◽  
Jonathan D. Brown ◽  
Amy J. Williams ◽  
Dean Falb ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Creb Binding Protein ◽  
Transcriptional Responses ◽  
Smad Proteins ◽  
Smad Protein

The transforming growth factor-β (TGF-β) superfamily of growth factors and cytokines has been implicated in a variety of physiological and developmental processes within the cardiovascular system. Smad proteins are a recently described family of intracellular signaling proteins that transduce signals in response to TGF-β superfamily ligands. We demonstrate by both a mammalian two-hybrid and a biochemical approach that human Smad2 and Smad4, two essential Smad proteins involved in mediating TGF-β transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator CREB binding protein (CBP). This interaction is specific in that it requires ligand (TGF-β) activation and is mediated by the transcriptional activation domains of the Smad proteins. A closely related, but distinct endothelial-expressed Smad protein, Smad7, which does not activate transcription in endothelial cells, does not interact with CBP. Furthermore, Smad2,4–CBP interactions involve the COOH terminus of CBP, a region that interacts with other regulated transcription factors such as certain signal transduction and transcription proteins and nuclear receptors. Smad–CBP interactions are required for Smad-dependent TGF-β-induced transcriptional responses in endothelial cells, as evidenced by inhibition with overexpressed 12S E1A protein and reversal of this inhibition with exogenous CBP. This report demonstrates a functional interaction between Smad proteins and an essential component of the mammalian transcriptional apparatus (CBP) and extends our insight into how Smad proteins may regulate transcriptional responses in many cell types. Thus, functional Smad–coactivator interactions may be an important locus of signal integration in endothelial cells.

scholarly journals E1A Inhibits Transforming Growth Factor-β Signaling through Binding to Smad Proteins

1999 ◽  
Vol 274 (40) ◽  
pp. 28716-28723 ◽  
Author(s):  
Ayako Nishihara ◽  
Jun-ichi Hanai ◽  
Takeshi Imamura ◽  
Kohei Miyazono ◽  
Masahiro Kawabata
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Smad Proteins

scholarly journals Ski-interacting Protein Interacts with Smad Proteins to Augment Transforming Growth Factor-β-dependent Transcription

2001 ◽  
Vol 276 (21) ◽  
pp. 18243-18248 ◽  
Author(s):  
Gary M. Leong ◽  
Nanthakumar Subramaniam ◽  
Jonine Figueroa ◽  
Judith L. Flanagan ◽  
Michael J. Hayman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interacting Protein ◽  
Smad Proteins

scholarly journals Competition between Ski and CREB-binding Protein for Binding to Smad Proteins in Transforming Growth Factor-β Signaling

2007 ◽  
Vol 282 (15) ◽  
pp. 11365-11376 ◽  
Author(s):  
Weijun Chen ◽  
Suvana S. Lam ◽  
Hema Srinath ◽  
Celia A. Schiffer ◽  
William E. Royer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Creb Binding Protein ◽  
Smad Proteins

scholarly journals The Integral Inner Nuclear Membrane Protein MAN1 Physically Interacts with the R-Smad Proteins to Repress Signaling by the Transforming Growth Factor-β Superfamily of Cytokines

2005 ◽  
Vol 280 (16) ◽  
pp. 15992-16001 ◽  
Author(s):  
Deng Pan ◽  
Luis D. Estévez-Salmerón ◽  
Shannon L. Stroschein ◽  
Xueliang Zhu ◽  
Jun He ◽  
...  
Keyword(s):  
Growth Factor ◽  
Membrane Protein ◽  
Nuclear Membrane ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin Signaling ◽  
Inner Nuclear Membrane ◽  
Smad Proteins ◽  
Inner Nuclear Membrane Protein ◽  
Nuclear Membrane Protein

Smad proteins are critical intracellular mediators of the transforming growth factor-β, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-Smads are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-Smads then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-Smad function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-Smads. MAN1, through the RNA recognition motif, associates with R-Smads but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-Smad phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFβ, BMP2, and activin-responsive promoters. This repression of TGFβ, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-Smad regulators and defines a previously unrecognized regulatory step at the nuclear periphery.

scholarly journals Eps15R is required for bone morphogenetic protein signalling and differentially compartmentalizes with Smad proteins

Open Biology ◽  
2012 ◽  
Vol 2 (4) ◽  
pp. 120060 ◽  
Author(s):  
Elizabeth M. Callery ◽  
Chong Yon Park ◽  
Xin Xu ◽  
Haitao Zhu ◽  
James C. Smith ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Proteins ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Adaptor Protein ◽  
Transforming Growth Factor Β ◽  
Morphogenetic Protein ◽  
Smad Proteins ◽  
Epidermal Growth ◽  
Bmp Signalling

Transforming growth factor β superfamily members signal through Smad transcription factors. Bone morphogenetic proteins (BMPs) act via Smads 1, 5 and 8 and TGF-βs signal through Smads 2 and 3. The endocytic adaptor protein Eps15R, or ‘epidermal growth factor (EGF) receptor pathway substrate 15-related protein’ is a component of EGF signal transduction, mediating internalization of the EGF receptor. We show that it interacts with Smad proteins, is required for BMP signalling in animal caps and stimulates Smad1 transcriptional activity. This function resides in the Asp-Pro-Phe motif-enriched ‘DPF domain’ of Eps15R, which activates transcription and antagonizes Smad2 signalling. In living cells, Eps15R segregates into spatially distinct regions with different Smads, indicating an unrecognized level of Smad compartmentalization.

scholarly journals Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor β-Mediated Transcription Repression

2008 ◽  
Vol 28 (6) ◽  
pp. 1988-1998 ◽  
Author(s):  
Deepti Srinivas Wilkinson ◽  
Wen-Wei Tsai ◽  
Maria A. Schumacher ◽  
Michelle Craig Barton
Keyword(s):  
Growth Factor ◽  
Tumor Marker ◽  
Transforming Growth Factor ◽  
Hepatoma Cell ◽  
Transforming Growth Factor Β ◽  
Regulatory Elements ◽  
Transcription Repression ◽  
Protein Levels ◽  
Smad Proteins ◽  
Distal Promoter

ABSTRACT In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, an oncodevelopmental tumor marker aberrantly reactivated in hepatoma cells. Using p53- and SnoN-depleted hepatoma cell clones, we define a mechanism for repression mediated by this novel transcriptional partnership. We find that p53 anchors activated Smads and the corepressor mSin3A to the AFP distal promoter. Sequential chromatin immunoprecipitation analyses and molecular modeling indicate that p53 and Smad proteins simultaneously occupy overlapping p53 and Smad regulatory elements to establish repression of AFP transcription. In addition to its well-known function in antagonizing transforming growth factor β (TGF-β) responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF-β signaling restores a dynamic interplay between p53 and TGF-β effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression.

Sign in / Sign up

Export Citation Format

Share Document