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.
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We are grateful to R. Brent for the yeast two-hybrid system; and to X. Yang for Daxx plasmids and discussions. We thank F. Chen, W. Vale, D. Riddle, X. Liu, J. Kyriakis and R. Lin for plasmids; D. W. Scott for CH33 cells; N. Fausto for AML12 cells; F. McKeon for anti-lamin 1E4 monoclonal antibodies; G. Paradis and M. Jennings for flow cytometry; P. Salomoni and P. Pandolfi for discussions and sharing unpublished results; and B. Osborne, S. Stewart and A. Sherman for reading the manuscript. We are especially grateful to M. Chen for her help, and all members of the Weinberg and Lodish laboratories. R.P. would like to express special thanks to A. Sherman for his advice, help and support. This work was supported by an NIH/NCI grant to R.A.W. and an NIH grant to H.F.L. R.P. was supported by the Israel Cancer Research Foundation, Human Frontiers Science Program and Cancer Research Foundation of America postdoctoral fellowships. W.P.S. was supported by the National Cancer Institute postdoctoral fellowship. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.
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