Disease relevance of DAXX

• The location of DAXX is of interest given the linkage of autoimmune disease to the MHC and to apoptosis [1].
• Adenovirus E1B 55-kilodalton oncoprotein binds to Daxx and eliminates enhancement of p53-dependent transcription by Daxx [2].
• DAXX interacts with phage PhiC31 integrase and inhibits recombination [3].
• Daxx accumulates in both the nucleus and the cytoplasm; in the nucleus, Daxx is found associated with the promyelocytic leukaemia (PML) nuclear body and with alpha-thalassemia/mental retardation syndrome protein (ATRX)-positive heterochromatic regions [4].
• The Pax3-FKHR fusion is unresponsive to this repressive effect despite an observed endogenous interaction with hDaxx in a rhabdomyosarcoma tumor cell line [5].

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

• To clarify these matters, we have used RNAi to deplete endogenous DAXX and thereby assess DAXX function in cell lines previously tested in overexpression studies [10].
• Furthermore, the increased levels of apoptosis observed in Daxx-knockout embryos and embryonic stem cell lines suggested that DAXX functions in an anti-apoptotic capacity [10].
• We employed RNA interference to downregulate Daxx in primary fibroblasts [11].
• Moreover, immunofluorescence analysis unequivocally demonstrated that MSP58 overexpression results in a translocation of Daxx to the enlarged nucleoli in COS-1 or 293 cells, whereas Daxx exhibited a diffuse nuclear pattern in HeLa cells [12].
• Similarly, in HCT116 cells, Daxx conferred striking resistance to 5-fluorouracil-induced apoptosis [13].

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

• Biochemical and immunofluorescence analyses reveal that Daxx is a nuclear protein that interacts and colocalizes with PML in the PODs [20].

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

• Data from immunofluorescence staining and protein interaction assay suggest that phosphorylated Daxx may be translocated to the cytoplasm, bind to ASK1, and subsequently lead to ASK1 oligomerization [14].
• The strong interaction between DAXX and PhiC31 was further confirmed by co-immunoprecipitation [3].
• Daxx also forms complexes with RelB while bound to its target sites in the cIAP2 promoter, as shown by electrophoretic mobility shift assays and chromatin immunoprecipitation experiments [26].
• Furthermore, chromatin immunoprecipitation analyses revealed the recruitment of Daxx to an endogenous, Smad4-targeted promoter in a Lys(159) sumoylation-dependent manner [27].
• Sentrin interacted with Daxx but not with FADD when analyzed by yeast two-hybrid assay [28].

References