Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-beta signaling in activated T lymphocytes.
Blood
; 109(7): 2944-52, 2007 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-17164348
ABSTRACT
Quiescent T cells express Tob, an APRO gene family member, which functions as a transcriptional regulator. Subtractive hybridization identified Twisted gastrulation (Tsg) as one of the genes suppressed by Tob. Tsg is a secreted protein that interacts with Drosophila decapentaplegic (Dpp) and its vertebrate orthologs BMP2/4 and regulates morphogenetic effects in embryos. Here, we report the expression and function of Tsg in human T cells. Tsg mRNA was almost undetectable in unstimulated T cells and was up-regulated after activation by TCR/CD3 and either CD28, IL-2, or PMA. Tsg protein had no effect on responses of primary T cells to TCR/CD3 stimulation but had a potent inhibitory effect on proliferation and cytokine production of primed alloreactive CD4+ cells. Surprisingly, Tsg did not affect phosphorylation of the BMP-specific Smad1 but induced phosphorylation of the TGF-beta-specific Smad2 and mediated DNA binding on Smad3/4 consensus-binding sites, suggesting that it acted downstream of TGF-beta. In vitro association assays revealed a direct interaction of Tsg and TGF-beta proteins. Thus, Tsg functions as an agonist synergizing with TGF-beta to inhibit T-cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
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Proteínas
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Fator de Crescimento Transformador beta
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Proteínas Supressoras de Tumor
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Peptídeos e Proteínas de Sinalização Intracelular
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article