Abstract
Transforming growth factor-beta (TGF-beta) controls a wide spectrum of cellular processes. Deregulation of TGF-beta signaling contributes to the pathogenesis of many diseases including cancer and autoimmune diseases. TGF-beta signaling is generally mediated through intracellular signal transducers and transcription factors called Smads. Herein, we have identified the oncoprotein BCL6 as a transcriptional corepressor of tumor suppressor Smad4. BCL6 physically interacts with Smad3 and Smad4, disrupts the Smad-p300 interaction, and represses the transcriptional activity of Smad4. In accordance, B-cell lymphoma cells with a high expression level of BCL6 were found to be refractory to TGF-beta antiproliferative response, whereas knockdown of BCL6 expression in B-cell lymphoma cells partially restores the TGF-beta responses. This study provides strong evidence that overexpression of BCL6 contributes to TGF-beta resistance in B-cell lymphoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Burkitt Lymphoma / drug therapy
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Burkitt Lymphoma / genetics
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Burkitt Lymphoma / metabolism*
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Burkitt Lymphoma / pathology
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Cell Growth Processes / drug effects
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Chromatin / metabolism
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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E1A-Associated p300 Protein / metabolism
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Humans
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Lymphoma, B-Cell / drug therapy
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism*
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Lymphoma, B-Cell / pathology
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Proto-Oncogene Proteins c-bcl-6
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RNA, Small Interfering / genetics
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Rats
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Signal Transduction
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Smad4 Protein / genetics
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Smad4 Protein / metabolism*
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Transcription, Genetic
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
Substances
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BCL6 protein, human
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Chromatin
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DNA-Binding Proteins
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Proto-Oncogene Proteins c-bcl-6
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RNA, Small Interfering
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SMAD4 protein, human
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Smad4 Protein
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Transforming Growth Factor beta
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E1A-Associated p300 Protein
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EP300 protein, human