Death associated protein 6

Introduction

DAXX ,a Death-Domain-Associated Protein, was first discovered as an interacting protein of the Fas-receptor. In other words, DAXX plays a major role in apoptosis. But, the protein is also active in the nucleus, where it is associated to some subnuclear domains like heterochromatin and PML-NB (Promyelocytic Leukaemia Nuclear Body).

tructure and Localization

DAXX is almost uniformally expressed throughout the body, except the testes and thymus have higher expression of the protein. At the level of the cell, DAXX is found as well in the cytoplasm, interacting with Fas-receptor or other cytoplasmic molecules, as in the nucleus where it is interacting with some subnuclear structures. A lot of other interacting molecules are known, but not always, there is an understanding of the specific function and relevance of this interaction.

Interacting partners

When the PML-NB are absent or disrupted, DAXX is delocalized and apoptosis does not occur. This was proven when PML-NB disrupted cells were treaten and DAXX relocalized with the PML-NB.ATRX, a centromeric heterochromatin component co-localizes with DAXX. This partnership is mainly found in the S-phase of the cell cycle. No expression of DAXX leads to malfunction of S phase and cells with two nuclei are formed. Another centromeric component, CENP-C, associates with DAXX during interphase. While at first, DAXX was said to be a “death protein”, it is suggested that associating with centromeric components leads to another function of DAXX.

Other binding partners are located in the cytoplasm or in the cell membrane

Fas-receptor stimulation causes Daxx to relocalize out of the nucleus and into the cytoplasma. The breakdown of glucose produces Reactive Oxygen Species(ROS).These induce extracellular Daxx to translocalize into the cytoplasma following an association with ASK1( Apoptosis signal-regulating kinase1). Another mechanism for exogenous Daxx import, consists out of CRM1. This transport is phophorylation dependent.Nevertheless, there is no exclusion whether the Fas-receptor stimuli or the ASK1 overexpression are caused by ROS or CRM1 mediated export.

Function and role of Daxx in Apoptosis

Fas-induced Apoptosis

After Fas stimulation,Daxx is activated and plays its role of pro-apoptotic protein in activating the c-JUN-N-Terminal Kinase(JNK) pathway.This pathway normally regulates stress induced cell death, it is also essential for development of nerval system by programmed cell death. The real apoptotic process starts after activating this pathway. Daxx does not activate JNK itself but rather the upstream JNK kinase kinase ASK1. Some kind of positive feedback system was also discovered; JNK activates HIPK2, which stands for the translocation of nuclear Daxx to the cytoplasm.In turn Daxx activates ASK1 again.

TGF-β regulated Apoptosis

TGF-β regulates a lot of different cell processes concerning development. Cell growth, differentiation, proliferation and cell death are the most important among those processes. It is proven that Daxx interacts with the TGF-β type II receptor by binding of C-terminal domain of the protein. When the cell is treated with TGF-β, HIPK2 which is a nuclear kinase, phosphorylates Daxx and starts participating in the JNK pathway.See figure "The Daxx Pathway"

Other induced Apoptosis

As said before, glucose breakdown produces ROS, which leads to Daxx production and relocalization, activating JNK pathway in turn. Another inducer of Daxx production is the exposure to UV-radiation.ASK1 will be transported to the nucleus when UV-irradiation is used to treat the cell. It is still unknown whether ASK1 binds Daxx, dute to UV-irradiation.Another important cell death-property of Daxx is the association with PML-NB. It was shown that Daxx only associates with Pml, when exposed to high oxidative stress or UV-irradiation. Another study showed loss of Daxx pro-apoptotic function in case of a mutant without Pml.

Anti-Apoptotic Functions of Daxx

A rather surprising property of Daxx is its anti-apoptotic function. When Daxx was not expressed or disrupted during embryonic development, it resulted in an early stage lethality. Other studies showed that lack of Daxx gene, caused a higher apoptotic rate in embryonic stem cells.Only when Daxx was bounded to Pml, Apoptosis rate were higher. Suggesting that cytoplasmic Daxx, associtated to cytoplasmic molecules has the role of an anti-apoptotic molecule.

Other Functions of Daxx

Transcriptional Regulation

The omnipresence of Daxx in the nucleus can give the impression that the protein can also be a transcription factor. Although there it contains no known DNA binding domains, Daxx can interact and suppress several transcription factors, such as P53, P73, NF-κB. Proteins other than transcription factors are also blocked or inhibited by Daxx, such as the TGF-β pathway regulator, Smad4, conferring upon Daxx a major role in TGF-β signaling.

External links

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Further reading

PBB_Further_reading
citations =
*cite journal | author=Paolo Salomoni and Amel F Khelifi |title=Daxx: death or survival protein? |journal=Trends in Cell Biology |volume=16 |issue= 2 |pages= 97–104 |year= 2005 |pmid= 8125298 |doi=
*cite journal | author=Yang X, Khosravi-Far R, Chang HY, Baltimore D |title=Daxx, a novel Fas-binding protein that activates JNK and apoptosis. |journal=Cell |volume=89 |issue= 7 |pages= 1067–76 |year= 1997 |pmid= 9215629 |doi=
*cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, "et al." |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=
*cite journal | author=Ishov AM, Sotnikov AG, Negorev D, "et al." |title=PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. |journal=J. Cell Biol. |volume=147 |issue= 2 |pages= 221–34 |year= 1999 |pmid= 10525530 |doi=
*cite journal | author=Li H, Leo C, Zhu J, "et al." |title=Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. |journal=Mol. Cell. Biol. |volume=20 |issue= 5 |pages= 1784–96 |year= 2000 |pmid= 10669754 |doi=
*cite journal | author=Zhong S, Salomoni P, Ronchetti S, "et al." |title=Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. |journal=J. Exp. Med. |volume=191 |issue= 4 |pages= 631–40 |year= 2000 |pmid= 10684855 |doi=
*cite journal | author=Li R, Pei H, Watson DK, Papas TS |title=EAP1/Daxx interacts with ETS1 and represses transcriptional activation of ETS1 target genes. |journal=Oncogene |volume=19 |issue= 6 |pages= 745–53 |year= 2000 |pmid= 10698492 |doi= 10.1038/sj.onc.1203385
*cite journal | author=Charette SJ, Lavoie JN, Lambert H, Landry J |title=Inhibition of Daxx-mediated apoptosis by heat shock protein 27. |journal=Mol. Cell. Biol. |volume=20 |issue= 20 |pages= 7602–12 |year= 2000 |pmid= 11003656 |doi=
*cite journal | author=Perlman R, Schiemann WP, Brooks MW, "et al." |title=TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. |journal=Nat. Cell Biol. |volume=3 |issue= 8 |pages= 708–14 |year= 2001 |pmid= 11483955 |doi= 10.1038/35087019

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