TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation

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Abstract
Transforming growth factor-β (TGF-β) 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-β 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-β-induced apoptosis in B-cell lymphomas, and antisense oligonucleotides to Daxx inhibit TGF-β-induced apoptosis in mouse hepatocytes. Furthermore, Daxx is involved in mediating JNK activation by TGF-β. Our findings associate Daxx directly with the TGF-β apoptotic-signalling pathway, and make a biochemical connection between the receptors for TGF-β and the apoptotic machinery.