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 fact or that has a principal role in growth control through both its cytostatic effect on many different epithelial cell types and its ability to induce pr ogrammed cell death in a variety of other cell types. Here we have used a s creen 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-ter minal kinase (JNK) and programmed cell death induced by Fas. The carboxy-te rminal portion of Daxx functions as a dominant-negative inhibitor of TGF-be ta -induced apoptosis in B-cell lymphomas, and antisense oligonucleotides t o Daxx inhibit TGF-beta -induced apoptosis in mouse hepatocytes. Furthermor e, Daxx is involved in mediating JNK activation by TGF-beta. Our findings a ssociate Daxx directly with the TGF-beta apoptotic-signalling pathway, and make a biochemical connection between the receptors for TGF-beta and the ap optotic machinery.