scholarly journals Involvement of the constitutive complex formation of c-Ski/SnoN with smads in the impaired negative feedback regulation of transforming growth factor β signaling in scleroderma fibroblasts

2007 ◽  
Vol 56 (5) ◽  
pp. 1694-1705 ◽  
Author(s):  
Masatoshi Jinnin ◽  
Hironobu Ihn ◽  
Yoshihiro Mimura ◽  
Yoshihide Asano ◽  
Kunihiko Tamaki
Keyword(s):  
Growth Factor ◽  
Complex Formation ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Feedback Regulation ◽  
Transforming Growth Factor Β ◽  
Negative Feedback Regulation

scholarly journals Smad7 Antagonizes Transforming Growth Factor β Signaling in the Nucleus by Interfering with Functional Smad-DNA Complex Formation

2007 ◽  
Vol 27 (12) ◽  
pp. 4488-4499 ◽  
Author(s):  
Suping Zhang ◽  
Teng Fei ◽  
Lixia Zhang ◽  
Ran Zhang ◽  
Feng Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Feedback Regulation ◽  
Transforming Growth Factor Β ◽  
Binding Activity ◽  
Type I ◽  
Negative Feedback Regulation ◽  
Dna Complex

ABSTRACT Smad7 plays an essential role in the negative-feedback regulation of transforming growth factor β (TGF-β) signaling by inhibiting TGF-β signaling at the receptor level. It can interfere with binding to type I receptors and thus activation of receptor-regulated Smads or recruit the E3 ubiquitin ligase Smurf to receptors and thus target them for degradation. Here, we report that Smad7 is predominantly localized in the nucleus of Hep3B cells. The targeted expression of Smad7 in the nucleus conferred superior inhibitory activity on TGF-β signaling, as determined by reporter assay in mammalian cells and by its effect on zebrafish embryogenesis. Furthermore, Smad7 repressed Smad3/4-, Smad2/4-, and Smad1/4-enhanced reporter gene expression, indicating that Smad7 can function independently of type I receptors. An oligonucleotide precipitation assay revealed that Smad7 can specifically bind to the Smad-responsive element via its MH2 domain, and DNA-binding activity was further confirmed in vivo with the promoter of PAI-1, a TGF-β target gene, by chromatin immunoprecipitation. Finally, we provide evidence that Smad7 disrupts the formation of the TGF-β-induced functional Smad-DNA complex. Our findings suggest that Smad7 inhibits TGF-β signaling in the nucleus by a novel mechanism.

scholarly journals Transforming growth factor-β-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis

2011 ◽  
Vol 103 (1) ◽  
pp. 26-33 ◽  
Author(s):  
Masaki Nakamura ◽  
Jiro Kitaura ◽  
Yutaka Enomoto ◽  
Yang Lu ◽  
Koutarou Nishimura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Feedback Regulator

SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2657-2665 ◽  
Author(s):  
Katarzyna Mleczko-Sanecka ◽  
Guillem Casanovas ◽  
Anan Ragab ◽  
Katja Breitkopf ◽  
Alexandra Müller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Iron Metabolism ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Protein

Abstract Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-β and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-β. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.

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