Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta -induced growth inhibition and apoptosis
| Autor: | Philip H. Howe, Gary M. Wildey, Rik Derynck, Supriya Patil, Tom Brown, Lisa Choy |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Programmed cell death
Lymphoma B-Cell Apoptosis Smad2 Protein Inhibitory postsynaptic potential Transfection Biochemistry Cell Line Smad7 Protein chemistry.chemical_compound Transactivation Pyrrolidine dithiocarbamate Antigens CD Transforming Growth Factor beta Tumor Cells Cultured Humans CD40 Antigens Phosphorylation Molecular Biology Cell Nucleus B-Lymphocytes CD40 integumentary system biology Cell Biology DNA-Binding Proteins chemistry Gene Expression Regulation biology.protein Cancer research Trans-Activators Growth inhibition Cell Division Transforming growth factor Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 275(49) |
| ISSN: | 0021-9258 |
| Popis: | Transforming growth factor-beta (TGF-beta) is a potent inducer of apoptosis in B-lymphocytes and is essential for immune regulation and maintenance of self-tolerance. Here we show that concomitant signaling through CD40 sustains proliferation and rescues the premature B cell line WEHI 231 from both TGF-beta-induced and anti-IgM-induced apoptosis. The anti-apoptotic effect of CD40 is associated with the transcriptional activation of the inhibitory Smad7 protein. The transactivation of Smad7 by CD40 is NFkappaB-dependent in that pharmacological inhibitors of this pathway, N-tosyl-l-phenylalanine chloromethyl ketone and pyrrolidine dithiocarbamate, abrogate CD40-induced Smad7 expression. Ectopic overexpression of Smad7 inhibited Smad2 activation, TGF-beta-mediated growth inhibition, and apoptosis in WEHI 231 cells. Consistent with this result, dominant negative interference with Smad2 and Smad3 function also inhibited TGF-beta-induced apoptosis. The inhibitory effects of Smad7 overexpression were specific to TGF-beta-induced apoptosis and were without effect on anti-IgM-induced cell death. These results suggest a mechanism of suppression of TGF-beta-induced apoptosis by CD40, mediated through activation of NF-kappaB and, consequently, induction of Smad7 expression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|