TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.
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.
Pubmed ID: 11483955 RIS Download
Adaptor Proteins, Signal Transducing | Animals | Antigens, CD95 | Apoptosis | COS Cells | Carrier Proteins | Cell Compartmentation | Cell Division | Hepatocytes | Humans | Intracellular Signaling Peptides and Proteins | Lymphoma, B-Cell | Mitogen-Activated Protein Kinase 8 | Mitogen-Activated Protein Kinases | Nuclear Proteins | Oligonucleotides, Antisense | Protein Structure, Tertiary | Protein-Serine-Threonine Kinases | Receptors, Transforming Growth Factor beta | Signal Transduction | Transforming Growth Factor beta | Tumor Cells, Cultured | Two-Hybrid System Techniques | Yeasts