TGF-β's Deadly Connection

Abstract

Transforming growth factor-β causes apoptosis in certain cell types, including lymphocytes and hepatocytes, but it has not been known how TGF-β receptors are coupled to the process of cell death. Searching for proteins that might do the job, Perlman et al. isolated the adapter protein Daxx in a yeast two-hybrid screen for human proteins that interacted with the type II TGF-β receptor. Daxx functions to link a different receptor--Fas (a member of the tumor necrosis factor receptor family)--to activation of the c-Jun NH 2 -terminal kinase (JNK) and subsequent programmed cell death. The authors found that endogenous Daxx associated with endogenous TGF-β receptor type II in a murine hepatocyte cell line. Antisense oligonucleotides to Daxx mRNA protected these cells from TGF-β-induced apoptosis. In a murine B-cell lymphoma cell line, a dominant-negative deletion mutant of Daxx inhibited apoptosis induced by TGF-β or Fas. Although many actions of TGF-β result from coupling of the receptor to the Smad proteins, which control transcription of target genes, or to other signaling proteins, the findings of Perlmann et al. indicate that the growth factor's apoptotic effects are mediated primarily by Daxx. R Perlman, W. P. Schiemann, M. W. Brooks, H. F. Lodish, R. A. Weinberg, TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nature Cell Biol. 3 , 708-714 (2001). [Online Journal]