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Gene Review

DAXX  -  death-domain associated protein

Homo sapiens

Synonyms: BING2, DAP6, Daxx, Death domain-associated protein 6, EAP1, ...
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Disease relevance of DAXX


High impact information on DAXX

  • Fas activation induced Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity [6].
  • The Fas death receptor can activate the Jun NH2-terminal kinase (JNK) pathway through the receptor-associated protein Daxx [6].
  • Surprisingly, rather than a hyperproliferative disorder expected from the loss of a pro-apoptotic gene, mutation of Daxx results in extensive apoptosis and embryonic lethality [7].
  • The death domain-associated protein (Daxx) was originally cloned as a CD95 (FAS)-interacting protein and modulator of FAS-induced cell death [4].
  • Despite a significant number of studies attempting to determine Daxx function in apoptotic and non-apoptotic cell death, its precise role in this process is only partially understood [4].

Biological context of DAXX

  • DAXX, a modulator of apoptosis and a repressor of basal transcription, was identified in a two-hybrid screen as a protein capable of interacting with a trimeric form of human heat shock factor 1 (HSF1) [8].
  • These observations suggest a model in which DAXX released from its nuclear stores during stress opposes repression of HSF1 transactivation competence by multichaperone complex through its interaction with trimerized HSF1 [8].
  • Up-regulation of surface FasL expression, accompanied by a down-regulation of Fas-associated proteins (FADD, DAXX, and RIP), was observed 72 h after infection [9].
  • Targeted deletion in the mouse revealed that DAXX is essential for embryonic development [10].
  • Remarkably, Daxx-depleted cells are resistant to cell death induced by both UV irradiation and oxidative stress [11].

Anatomical context of DAXX


Associations of DAXX with chemical compounds

  • The relocalized Daxx may play an important role in glucose deprivation-induced ASK1 oligomerization [14].
  • However, SB203580, a p38 inhibitor, did not prevent relocalization of Daxx and oligomerization of ASK1 during glucose deprivation [14].
  • Mutation of three potential phosphorylation sites (S489/490 and T494 to alanine) within the E1B 55-kDa protein did not affect its interaction with Daxx, although such mutations were previously shown to inhibit E1B's ability to repress p53-dependent transcription and to enhance transformation [2].
  • Upon retinoic acid treatment, which induces disease remission in APL, Daxx relocalizes to the PML NBs [15].
  • Arsenic trioxide (As(2)O(3)), an agent that accentuates POD formation, collaborated synergistically with overexpression of hDaxx to increase cellular sensitivity to Fas-induced apoptosis [16].

Physical interactions of DAXX

  • In human cells, DAXX interacted with HSF1 essentially only during stress, i.e., when factor trimerization occurred [8].
  • Daxx binds to ATRX through its paired amphipathic alpha helices domains [17].
  • Indeed, PML overexpression led to dramatic redistribution of Daxx from p53-E1B 55-kDa protein complexes to PML bodies [2].
  • Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation [18].
  • TSG101 formed a complex with Daxx through its coiled-coil domain and co-localized in the nucleus [19].

Co-localisations of DAXX


Regulatory relationships of DAXX

  • Overexpressed HSF1, known to be largely trimeric, only marginally increased HSF1 activity on its own but potentiated the activating effect of DAXX overexpression [8].
  • This is the first evidence that Daxx promotes cell death and JNK activation in physiological conditions [11].
  • These results suggest that FADD and Daxx activate two independent pathways downstream of Fas and confirm the essential role of FADD binding in apoptosis induction [21].
  • Through this interaction hDaxx represses the transcriptional activity of Pax3 by approximately 80% [5].
  • These data strongly suggest that Daxx may inhibit Fas and stress-mediated apoptosis by suppressing proapoptotic gene expression outside of PML domains [22].
  • These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis [23].
  • Based on the results, we propose that ischemic insult triggers the nucleocytoplasmic translocation of Daxx, following which cytoplasmic Daxx stimulates the NHE1 transporter activity and suppresses activation of the NHE1-ezrin-Akt-1 pathway [24].

Other interactions of DAXX

  • In the absence of PML, Daxx is highly enriched in condensed chromatin [25].
  • We identified the adapter protein Daxx and BML, the RecQ helicase missing in Bloom syndrome, as new ND10-associated proteins [25].
  • Expression of a nonnative protein capable of competing for multichaperone complex also synergistically enhanced activation of HSF1 by DAXX [8].
  • Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization [14].
  • Studies from in vivo labeling and immune complex kinase assay demonstrated that phosphorylation of Daxx occurred during glucose deprivation, and its phosphorylation was mediated through the ASK1-SEK1-JNK1-HIPK1 signal transduction pathway [14].

Analytical, diagnostic and therapeutic context of DAXX


  1. TAPASIN, DAXX, RGL2, HKE2 and four new genes (BING 1, 3 to 5) form a dense cluster at the centromeric end of the MHC. Herberg, J.A., Beck, S., Trowsdale, J. J. Mol. Biol. (1998) [Pubmed]
  2. Adenovirus E1B 55-kilodalton oncoprotein binds to Daxx and eliminates enhancement of p53-dependent transcription by Daxx. Zhao, L.Y., Colosimo, A.L., Liu, Y., Wan, Y., Liao, D. J. Virol. (2003) [Pubmed]
  3. DAXX interacts with phage PhiC31 integrase and inhibits recombination. Chen, J.Z., Ji, C.N., Xu, G.L., Pang, R.Y., Yao, J.H., Zhu, H.Z., Xue, J.L., Jia, W. Nucleic Acids Res. (2006) [Pubmed]
  4. Daxx: death or survival protein? Salomoni, P., Khelifi, A.F. Trends Cell Biol. (2006) [Pubmed]
  5. The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx. Hollenbach, A.D., Sublett, J.E., McPherson, C.J., Grosveld, G. EMBO J. (1999) [Pubmed]
  6. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Chang, H.Y., Nishitoh, H., Yang, X., Ichijo, H., Baltimore, D. Science (1998) [Pubmed]
  7. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Michaelson, J.S., Bader, D., Kuo, F., Kozak, C., Leder, P. Genes Dev. (1999) [Pubmed]
  8. DAXX interacts with heat shock factor 1 during stress activation and enhances its transcriptional activity. Boellmann, F., Guettouche, T., Guo, Y., Fenna, M., Mnayer, L., Voellmy, R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  9. HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism. Genini, D., Sheeter, D., Rought, S., Zaunders, J.J., Susin, S.A., Kroemer, G., Richman, D.D., Carson, D.A., Corbeil, J., Leoni, L.M. FASEB J. (2001) [Pubmed]
  10. RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX. Michaelson, J.S., Leder, P. J. Cell. Sci. (2003) [Pubmed]
  11. Daxx is required for stress-induced cell death and JNK activation. Khelifi, A.F., D'Alcontres, M.S., Salomoni, P. Cell Death Differ. (2005) [Pubmed]
  12. Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration. Lin, D.Y., Shih, H.M. J. Biol. Chem. (2002) [Pubmed]
  13. Negative regulation of p53 functions by Daxx and the involvement of MDM2. Zhao, L.Y., Liu, J., Sidhu, G.S., Niu, Y., Liu, Y., Wang, R., Liao, D. J. Biol. Chem. (2004) [Pubmed]
  14. Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization. Song, J.J., Lee, Y.J. J. Biol. Chem. (2003) [Pubmed]
  15. Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. Zhong, S., Salomoni, P., Ronchetti, S., Guo, A., Ruggero, D., Pandolfi, P.P. J. Exp. Med. (2000) [Pubmed]
  16. Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). Torii, S., Egan, D.A., Evans, R.A., Reed, J.C. EMBO J. (1999) [Pubmed]
  17. A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. Tang, J., Wu, S., Liu, H., Stratt, R., Barak, O.G., Shiekhattar, R., Picketts, D.J., Yang, X. J. Biol. Chem. (2004) [Pubmed]
  18. Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation. Kim, Y.Y., Park, B.J., Seo, G.J., Lim, J.Y., Lee, S.M., Kimm, K.C., Park, C., Kim, J., Park, S.I. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  19. Physical and functional interactions between Daxx and TSG101. Muromoto, R., Sugiyama, K., Yamamoto, T., Oritani, K., Shimoda, K., Matsuda, T. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  20. Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Li, H., Leo, C., Zhu, J., Wu, X., O'Neil, J., Park, E.J., Chen, J.D. Mol. Cell. Biol. (2000) [Pubmed]
  21. Dissecting Fas signaling with an altered-specificity death-domain mutant: requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation. Chang, H.Y., Yang, X., Baltimore, D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  22. Daxx silencing sensitizes cells to multiple apoptotic pathways. Chen, L.Y., Chen, J.D. Mol. Cell. Biol. (2003) [Pubmed]
  23. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. Kwon, J.E., La, M., Oh, K.H., Oh, Y.M., Kim, G.R., Seol, J.H., Baek, S.H., Chiba, T., Tanaka, K., Bang, O.S., Joe, C.O., Chung, C.H. J. Biol. Chem. (2006) [Pubmed]
  24. Physical interactions and functional coupling between Daxx and sodium hydrogen exchanger 1 in ischemic cell death. Jung, Y.S., Kim, H.Y., Kim, J., Lee, M.G., Pouysségur, J., Kim, E. J. Biol. Chem. (2008) [Pubmed]
  25. PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. Ishov, A.M., Sotnikov, A.G., Negorev, D., Vladimirova, O.V., Neff, N., Kamitani, T., Yeh, E.T., Strauss, J.F., Maul, G.G. J. Cell Biol. (1999) [Pubmed]
  26. Daxx Represses Expression of a Subset of Antiapoptotic Genes Regulated by Nuclear Factor-{kappa}B. Croxton, R., Puto, L.A., de Belle, I., Thomas, M., Torii, S., Hanaii, F., Cuddy, M., Reed, J.C. Cancer Res. (2006) [Pubmed]
  27. Daxx mediates the small ubiquitin-like modifier-dependent transcriptional repression of Smad4. Chang, C.C., Lin, D.Y., Fang, H.I., Chen, R.H., Shih, H.M. J. Biol. Chem. (2005) [Pubmed]
  28. Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9. Ryu, S.W., Chae, S.K., Kim, E. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
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