Death associated protein 6
Encyclopedia
Death-associated protein 6 also known as DAXX is a protein
that in humans is encoded by the DAXX gene
.
. It has been associated with heterochromatin
and PML-NBs (Promyelocytic Leukaemia nuclear bodies) and has been implicated in many nuclear processes including transcription and cell cycle
regulation.
This gene encodes a multifunctional protein that resides in multiple locations in the nucleus
and in the cytoplasm
. It interacts with a wide variety of proteins, such as apoptosis
antigen
Fas, centromere protein C
, and transcription factor erythroblastosis virus E26 oncogene homolog 1 (ETS1
). In the nucleus, the encoded protein functions as a potent transcription repressor that binds to sumoylated transcription factors. Its repression can be relieved by the sequestration of this protein into promyelocytic leukemia nuclear bodies or nucleoli
. This protein also associates with centromere
s in G2 phase
. In the cytoplasm, the encoded protein may function to regulate apoptosis. The subcellular localization and function of this protein are modulated by post-translational modifications, including sumoylation, phosphorylation and polyubiquitination.
, which have especially high expression of the protein. At the level of the cell, DAXX is found in the cytoplasm
, interacting with Fas-receptor or other cytoplasmic molecules, as well as in the nucleus
, where it is interacting with some subnuclear structures. Several additional interacting proteins are known, but not always is there an understanding of the specific function and relevance of this interaction.
ATRX
, a centromeric heterochromatin component co-localizes with DAXX. This partnership is found mainly 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.
out of the nucleus and into the cytoplasm. The breakdown of glucose produces reactive oxygen species (ROS
). These induce extracellular Daxx to translocalize into the cytoplasm following an association with ASK1
(Apoptosis signal-regulating kinase1). Another mechanism for exogenous Daxx import involves CRM1
. This transport mechanism is phophorylation dependent.
Nevertheless, it is not known whether the Fas-receptor stimuli or the ASK1 overexpression are caused by ROS or CRM1 mediated export.
. 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.
by binding of C-terminal domain of the protein. When the cell is treated with TGF-β, HIPK2
, a nuclear kinase, phosphorylates
Daxx and the activated Daxx in turn activates the JNK
pathway (see "The Daxx Pathway" figure).
ASK1 will be transported to the nucleus when UV-irradiation is used to treat the cell. It is still unknown as to whether ASK1 binds Daxx, due to UV-irradiation.
Another important cell death-property of Daxx is the association with PML-NB. It was shown that Daxx associates with Pml only 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.
Only when Daxx was bound to Pml were apoptosis rates higher, suggesting that associated cytoplasmic Daxx has the role of an anti-apoptotic molecule.
. Although it contains no known DNA-binding domain
s, Daxx can interact and suppress several transcription factors, such as p53
, p73
, and 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the DAXX gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
DAXX, a death-domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor FasFAS ligand
Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
. It has been associated with heterochromatin
Heterochromatin
Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
and PML-NBs (Promyelocytic Leukaemia nuclear bodies) and has been implicated in many nuclear processes including transcription and cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
regulation.
This gene encodes a multifunctional protein that resides in multiple locations in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. It interacts with a wide variety of proteins, such as apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
Fas, centromere protein C
CENPC1
Centromere protein C 1 is a protein that in humans is encoded by the CENPC1 gene.-Further reading:...
, and transcription factor erythroblastosis virus E26 oncogene homolog 1 (ETS1
ETS1
Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.-Interactions:ETS1 has been shown to interact with TTRAP, UBE2I and Death associated protein 6....
). In the nucleus, the encoded protein functions as a potent transcription repressor that binds to sumoylated transcription factors. Its repression can be relieved by the sequestration of this protein into promyelocytic leukemia nuclear bodies or nucleoli
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within the nucleolus...
. This protein also associates with centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
s in G2 phase
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...
. In the cytoplasm, the encoded protein may function to regulate apoptosis. The subcellular localization and function of this protein are modulated by post-translational modifications, including sumoylation, phosphorylation and polyubiquitination.
Structure and localization
DAXX is uniformally expressed throughout the body, except in the testes and thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, which have especially high expression of the protein. At the level of the cell, DAXX is found in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, interacting with Fas-receptor or other cytoplasmic molecules, as well as in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, where it is interacting with some subnuclear structures. Several additional interacting proteins are known, but not always is there an understanding of the specific function and relevance of this interaction.
Nuclear
When the PML-NB are absent or disrupted, DAXX is delocalized and apoptosis does not occur. This interaction was demonstrated when PML-NB disrupted cells were treaten and DAXX relocalized with the PML-NB.ATRX
ATRX
Transcriptional regulator ATRX also known as ATP-dependent helicase ATRX, X-linked helicase II, or X-linked nuclear protein is a protein that in humans is encoded by the ATRX gene.- Function :...
, a centromeric heterochromatin component co-localizes with DAXX. This partnership is found mainly 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
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...
. 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.
Cytoplasmic and membrane
Fas-receptor stimulation causes Daxx to translocateProtein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
out of the nucleus and into the cytoplasm. The breakdown of glucose produces reactive oxygen species (ROS
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
). These induce extracellular Daxx to translocalize into the cytoplasm following an association with ASK1
ASK1
Apoptosis signal-regulating kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway...
(Apoptosis signal-regulating kinase1). Another mechanism for exogenous Daxx import involves CRM1
XPO1
Exportin-1 is a protein that in humans is encoded by the XPO1 gene.-Interactions:XPO1 has been shown to interact with NMD3, CIITA, RANBP3, Nucleoporin 62, Ran, RANBP1, APC, SMARCB1 and CDKN1B.-Further reading:...
. This transport mechanism is phophorylation dependent.
Nevertheless, it is not known whether the Fas-receptor stimuli or the ASK1 overexpression are caused by ROS or CRM1 mediated export.
Fas-induced
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 ASK1ASK1
Apoptosis signal-regulating kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway...
. Some kind of positive feedback system was also discovered; JNK activates HIPK2
HIPK2
Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.-Interactions:HIPK2 has been shown to interact with SKI protein, Death associated protein 6, P53, CREB binding protein, Mothers against decapentaplegic homolog 1, TP53INP1 and RANBP9.-Further reading:...
, which stands for the translocation of nuclear Daxx to the cytoplasm. In turn, Daxx activates ASK1 again.
TGF-β regulated
TGF-β regulates a variety of different cellular developmental processes including growth, differentiation, proliferation, and cell death. Daxx interacts with the TGF-β type II receptorTGF beta receptor 2
Transforming growth factor, beta receptor II is a TGF beta receptor. TGFBR2 is its human gene.It is a tumor suppressor gene.-Interactions:...
by binding of C-terminal domain of the protein. When the cell is treated with TGF-β, HIPK2
HIPK2
Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.-Interactions:HIPK2 has been shown to interact with SKI protein, Death associated protein 6, P53, CREB binding protein, Mothers against decapentaplegic homolog 1, TP53INP1 and RANBP9.-Further reading:...
, a nuclear kinase, phosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
Daxx and the activated Daxx in turn activates the JNK
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
pathway (see "The Daxx Pathway" figure).
Miscellaneous mechanisms
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 as to whether ASK1 binds Daxx, due to UV-irradiation.
Another important cell death-property of Daxx is the association with PML-NB. It was shown that Daxx associates with Pml only when exposed to high oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
or UV-irradiation. Another study showed loss of Daxx pro-apoptotic function in case of a mutant without Pml.
Anti-apoptotic function
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 bound to Pml were apoptosis rates higher, suggesting that associated cytoplasmic Daxx has the role of an anti-apoptotic molecule.
Other functions
The omnipresence of Daxx in the cell nucleus suggests that the protein may also function as a transcription factorTranscription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
. Although it contains no known DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
s, Daxx can interact and suppress several transcription factors, such as p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, p73
P73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein...
, and NF-κB. Proteins other than transcription factors are also blocked or inhibited by Daxx, such as the TGF-β pathway
TGF beta signaling pathway
The Transforming growth factor beta signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular...
regulator, Smad4
Mothers against decapentaplegic homolog 4
SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily...
, conferring upon Daxx a major role in TGF-β signaling.