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

An Erratum to this article was published on 01 February 2002


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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Figure 1: Interaction of Daxx with TβRII and subcellular localization of Daxx.
Figure 2: Inhibitory effects of DaxxC on TGF-β-induced apoptosis.
Figure 3: TGF-β-induced apoptosis and JNK activation in AML12 cells.
Figure 4: Effects of Daxx and DaxxC on TGF-β-induced JNK activation.


  1. 1

    Massague, J. The transforming growth factor-β family. Annu. Rev. Cell Biol. 6, 597–641 (1990).

    CAS  Article  Google Scholar 

  2. 2

    Letterio, J. J. & Roberts, A. B. TGF-β: a critical modulator of immune cell function. Clin. Immunol. Immunopathol. 84, 244–250 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    CAS  Article  Google Scholar 

  4. 4

    Kulkarni, A. B. et al. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA 90, 770–774 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Dang, H. et al. SLE-like autoantibodies and Sjogren's syndrome-like lymphoproliferation in TGF-β knockout mice. J. Immunol. 155, 3205–3212 (1995).

    CAS  Google Scholar 

  6. 6

    Fischer, G., Kent, S. C., Joseph, L., Green, D. R. & Scott, D. W. Lymphoma models for B cell activation and tolerance. X. Anti-mu-mediated growth arrest and apoptosis of murine B cell lymphomas is prevented by the stabilization of myc. J. Exp. Med. 179, 221–228 (1994).

    CAS  Article  Google Scholar 

  7. 7

    Chaouchi, N. et al. Characterization of transforming growth factor-β1 induced apoptosis in normal human B cells and lymphoma B cell lines. Oncogene 11, 1615–1622 (1995).

    CAS  Google Scholar 

  8. 8

    Arsura, M., Wu, M. & Sonenshein, G. E. TGF β1 inhibits NF-κB/Rel activity inducing apoptosis of B cells: transcriptional activation of IκBα. Immunity 5, 31–40 (1996).

    CAS  Article  Google Scholar 

  9. 9

    McMahon, J. B., Richards, W. L., del Campo, A. A., Song, M. K. & Thorgeirsson, S. S. Differential effects of transforming growth factor-β on proliferation of normal and malignant rat liver epithelial cells in culture. Cancer Res. 46, 4665–4671 (1986).

    CAS  Google Scholar 

  10. 10

    Sanderson, N. et al. Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions. Proc. Natl Acad. Sci. USA 92, 2572–2576 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Arsura, M., Fitz Gerald, M. J., Fausto, N. & Sonenshein, G. E. Nuclear factor-κB/Rel blocks transforming growth factor β1-induced apoptosis of murine hepatocyte cell lines. Cell Growth Differ. 8, 1049–1059 (1997).

    CAS  Google Scholar 

  12. 12

    Jacobson, M. D., Weil, M. & Raff, M. C. Programmed cell death in animal development. Cell 88, 347–354 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Evan, G. & Littlewood, T. A matter of life and cell death. Science 281, 1317–1322 (1998).

    CAS  Article  Google Scholar 

  14. 14

    Abbas, A. K. Die and let live: eliminating dangerous lymphocytes. Cell 84, 655–657 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Massague, J. & Weis-Garcia, F. Serine/threonine kinase receptors: mediators of transforming growth factor β family signals. Cancer Surv. 27, 41–64 (1996).

    CAS  Google Scholar 

  17. 17

    Wieser, R., Wrana, J. L. & Massague, J. GS domain mutations that constitutively activate TβR-I, the downstream signaling component in the TGF-β receptor complex. EMBO J. 14, 2199–2208 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Derynck, R., Zhang, Y. & Feng, X. H. Smads: transcriptional activators of TGF-β responses. Cell 95, 737–740 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Atfi, A., Buisine, M., Mazars, A. & Gespach, C. Induction of apoptosis by DPC4, a transcriptional factor regulated by transforming growth factor-β through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling pathway. J. Biol. Chem. 272, 24731–24734 (1997).

    CAS  Article  Google Scholar 

  20. 20

    Chen, R. H. & Chang, T. Y. Involvement of caspase family proteases in transforming growth factor-β-induced apoptosis. Cell Growth Differ. 8, 821–827 (1997).

    CAS  Google Scholar 

  21. 21

    Brown, T. L., Patil, S., Basnett, R. K. & Howe, P. H. Caspase inhibitor BD-fmk distinguishes transforming growth factor β-induced apoptosis from growth inhibition. Cell Growth Differ. 9, 869–875 (1998).

    CAS  Google Scholar 

  22. 22

    Le Dai, J., Bansal, R. K. & Kern, S. E. G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation. Proc. Natl Acad. Sci. USA 96, 1427–1432 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Yang, X., Khosravi-Far, R., Chang, H. Y. & Baltimore, D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89, 1067–1076 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Chang, H. Y., Nishitoh, H., Yang, X., Ichijo, H. & Baltimore, D. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 281, 1860–1863 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Chang, H. Y., Yang, X. & Baltimore, D. Dissecting Fas signaling with an altered-specificity death-domain mutant: requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation. Proc. Natl Acad. Sci. USA 96, 1252–1256 (1999).

    CAS  Article  Google Scholar 

  26. 26

    Gyuris, J., Golemis, E., Chertkov, H. & Brent, R. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell 75, 791–803 (1993).

    CAS  Article  Google Scholar 

  27. 27

    Estevez, M. et al. The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature 365, 644–649 (1993).

    CAS  Article  Google Scholar 

  28. 28

    Torii, S., Egan, D. A., Evans, R. A. & Reed, J. C. Human daxx regulates fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J. 18, 6037–6049 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Goillot, E. et al. Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc. Natl Acad. Sci. USA 94, 3302–3307 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Michaelson, J. S., Bader, D., Kuo, F., Kozak, C. & Leder, P. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13, 1918–1923 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Chen, F. & Weinberg, R. A. Biochemical evidence for the autophosphorylation and transphosphorylation of transforming growth factor β receptor kinases. Proc. Natl Acad. Sci. USA 92, 1565–1569 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Wu, J. C., Merlino, G. & Fausto, N. Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor α. Proc. Natl Acad. Sci. USA 91, 674–678 (1994).

    CAS  Article  Google Scholar 

  33. 33

    Zhong, S. et al. Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J. Exp. Med. 191, 631–640 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Goodwin, G. H. Isolation of Nuclei 97–101 (Oxford Univ. Press, New York, 1989).

    Google Scholar 

  35. 35

    Chan, D. C. & Leder, P. Genetic evidence that formins function within the nucleus. J. Biol. Chem. 271, 23472–23477 (1996).

    CAS  Article  Google Scholar 

  36. 36

    Liu, X. et al. Transforming growth factor β-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc. Natl Acad. Sci. USA 94, 10669–10674 (1997).

    CAS  Article  Google Scholar 

  37. 37

    Yamaguchi, K. et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270, 2008–2011 (1995).

    CAS  Article  Google Scholar 

  38. 38

    Atfi, A., Djelloul, S., Chastre, E., Davis, R. & Gespach, C. Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in transforming growth factor β-mediated signaling. J. Biol. Chem. 272, 1429–1432 (1997).

    CAS  Article  Google Scholar 

  39. 39

    Wang, W., Zhou, G., Hu, M. C. T., Yao, Z. & Tan, T. H. Activation of the hematopoietic progenitor kinase-1 (HPK1)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor β (TGF-β)-activated kinase (TAK1), a kinase mediator of TGF β signal transduction. J. Biol. Chem. 272, 22771–22775 (1997).

    CAS  Article  Google Scholar 

  40. 40

    Choy, L. & Derynck, R. The type II transforming growth factor (TGF)-β receptor-interacting protein TRIP-1 acts as a modulator of the TGF-β response. J. Biol. Chem. 273, 31455–31462 (1998).

    CAS  Article  Google Scholar 

  41. 41

    Pear, W. S., Nolan, G. P., Scott, M. L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl Acad. Sci. USA 90, 8392–8396 (1993).

    CAS  Article  Google Scholar 

  42. 42

    Ullrich, A. & Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990).

    CAS  Article  Google Scholar 

  43. 43

    Pawson, T. & Gish, G. D. SH2 and SH3 domains: from structure to function. Cell 71, 359–362 (1992).

    CAS  Article  Google Scholar 

  44. 44

    Wang, T., Donahoe, P. K. & Zervos, A. S. Specific interaction of type I receptors of the TGF-β family with the immunophilin FKBP-12. Science 265, 674–676 (1994).

    CAS  Article  Google Scholar 

  45. 45

    Chen, R. H., Miettinen, P. J., Maruoka, E. M., Choy, L. & Derynck, R. A WD-domain protein that is associated with and phosphorylated by the type II TGF-β receptor. Nature 377, 548–552 (1995).

    CAS  Article  Google Scholar 

  46. 46

    Griswold-Prenner, I., Kamibayashi, C., Maruoka, E. M., Mumby, M. C. & Derynck, R. Physical and functional interactions between type I transforming growth factor β receptors and Bα, a WD-40 repeat subunit of phosphatase 2A. Mol. Cell. Biol. 18, 6595–6604 (1998).

    CAS  Article  Google Scholar 

  47. 47

    Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L. & Wrana, J. L. SARA, a FYVE domain protein that recruits Smad2 to the TGFβ receptor. Cell 95, 779–791 (1998).

    CAS  Article  Google Scholar 

  48. 48

    Yamaguchi, K. et al. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J. 18, 179–187 (1999).

    CAS  Article  Google Scholar 

  49. 49

    Wells, R. G. et al. Transforming growth factor-β induces formation of a dithiothreitol-resistant type I/Type II receptor complex in live cells. J. Biol. Chem. 274, 5716–5722 (1999).

    CAS  Article  Google Scholar 

  50. 50

    Sicinski, P. et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384, 470–474 (1996).

    CAS  Article  Google Scholar 

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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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Correspondence to Robert A. Weinberg.

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Perlman, R., Schiemann, W., Brooks, M. et al. TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3, 708–714 (2001).

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