Abstract
Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that has a principal role in growth control through both its cytostatic effect on many different epithelial cell types and its ability to induce programmed cell death in a variety of other cell types. Here we have used a screen for proteins that interact physically with the cytoplasmic domain of the type II TGF-beta receptor to isolate the gene encoding Daxx - a protein associated with the Fas receptor that mediates activation of Jun amino-terminal kinase (JNK) and programmed cell death induced by Fas. The carboxy-terminal portion of Daxx functions as a dominant-negative inhibitor of TGF-beta-induced apoptosis in B-cell lymphomas, and antisense oligonucleotides to Daxx inhibit TGF-beta-induced apoptosis in mouse hepatocytes. Furthermore, Daxx is involved in mediating JNK activation by TGF-beta. Our findings associate Daxx directly with the TGF-beta apoptotic-signalling pathway, and make a biochemical connection between the receptors for TGF-beta and the apoptotic machinery.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics*
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COS Cells / cytology
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COS Cells / drug effects
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COS Cells / metabolism
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Carrier Proteins / drug effects
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Compartmentation / drug effects
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Cell Compartmentation / genetics
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Cell Division / drug effects
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Cell Division / genetics*
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Co-Repressor Proteins
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins*
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / genetics*
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Chaperones
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Nuclear Proteins*
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Oligonucleotides, Antisense / pharmacology
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Protein Serine-Threonine Kinases
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Protein Structure, Tertiary / drug effects
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Protein Structure, Tertiary / genetics
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics*
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / genetics
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Transforming Growth Factor beta / genetics*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Two-Hybrid System Techniques
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Yeasts / drug effects
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Yeasts / genetics
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Yeasts / metabolism
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fas Receptor / drug effects
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Co-Repressor Proteins
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DAXX protein, human
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Daxx protein, mouse
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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Nuclear Proteins
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Oligonucleotides, Antisense
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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fas Receptor
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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Receptor, Transforming Growth Factor-beta Type II